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1 1 2 1 2 3 FOOD AND DRUG ADMINISTRATION 4 5 CENTER FOR DRUG EVALUATION AND RESEARCH 6 7 8 9 10 MEETING OF THE 11 12 ARTHRITIS ADVISORY COMMITTEE 13 14 15 16 17 18 19 20 21 22 23 24 25 8:05 a.m 26 27 Monday, June 23, 2003 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 1 2 2 1 Versailles Ballroom 2 Holiday Inn 3 8120 Wisconsin Avenue 4 Bethesda, Maryland 1 3 2 1 ATTENDEES 2 3 COMMITTEE MEMBERS: 4 5 GARY S. FIRESTEIN, M.D., Chair 6 Chief, Division of Rheumatology, 7 Allergy and Immunology 8 Department of Medicine 9 University of California at San Diego 10 9500 Gilman Drive 11 Basic Science Building, Room 5098 12 La Jolla, California 92093 13 14 JOHANNA M. CLIFFORD, M.S., R.N., B.S.N. 15 Advisors and Consultants Staff (HFD-21) 16 Center for Drug Evaluation and Research 17 Food and Drug Administration 18 5600 Fishers Lane, Building 5630, Room 1093 19 Rockville, Maryland 20857 20 21 JENNIFER J. ANDERSON, PH.D. 22 Research Professor of Public Health 23 Department of Epidemiology and Biostatistics 24 Boston University School of Medicine 25 A-203 26 715 Albany Street 27 Boston, Massachusetts 02118 28 29 JOHN J. CUSH, M.D. 30 Chief of Rheumatology and Clinical Immunology 31 Presbyterian Hospital 32 8200 Walnut Hill Lane 33 Dallas, Texas 75231-4496 34 35 WENDY McBRAIR, R.N., M.S., C.H.E.S. 36 Consumer Representative 37 Director 38 Southern New Jersey Regional Arthritis Center 39 Virtua Health 40 1 Carnie Boulevard 41 Voorhees, New Jersey 08043 42 43 HOWARD J. WILLIAMS, JR., M.D. 44 Department of Internal Medicine 1 4 2 1 Division of Rheumatology 2 University of Utah School of Medicine 3 50 North Medical Drive 4 Salt Lake City, Utah 84132 1 5 2 1 ATTENDEES (Continued) 2 3 CONSULTANTS: (Voting) 4 5 STEVEN ABRAMSON, M.D. 6 Chairman of Rheumatology and Immunology 7 Hospital for Joint Diseases 8 301 East 17th Street 9 New York, New York 10003 10 11 LAURENCE BRADLEY, PH.D. 12 Professor of Medicine 13 University of Alabama at Birmingham 14 467 Boshell Diabetes Building 15 Birmingham, Alabama 35294 16 17 ALLAN GIBOFSKY, M.D., J.D. 18 Hospital for Special Surgery 19 Weill Medical College 20 Cornell University 21 425 East 79th Street 22 New York, New York 10021 23 24 MICHAEL FINLEY, D.O. 25 Western University 26 College of Osteopathic Medicine 27 309 East Second Street 28 College Plaza 29 Pamona, California 91766-1854 30 31 GARY HOFFMAN, M.D., M.S. 32 Chairman, Department of Rheumatic and 33 Immunologic Diseases 34 The Cleveland Clinic Foundation A/50 35 9500 Euclid Avenue 36 Cleveland, Ohio 44195 37 38 NATHANIEL KATZ, M.D. 39 Assistant Professor of Anesthesiology 40 Harvard Medical School 41 Pain Trials Center 42 75 Francis Street 43 Boston, Massachusetts 02115 1 6 2 1 ATTENDEES (Continued) 2 3 CONSULTANTS: (Voting) 4 5 ROLAND STAUD, M.D. 6 Associate Professor of Medicine 7 University of Florida 8 Division of Rheumatology and 9 Clinical Immunology 10 1600 SW Archer Road 11 Gainesville, Florida 32610-0221 12 13 DENNIS TURK, PH.D. 14 Professor 15 Department of Anesthesiology 16 University of Washington 17 School of Medicine 18 1959 NE Pacific Street 19 Room BB1425, HSB 20 Seattle, Washington 91895-2958 21 22 23 CONSULTANTS: (Non-voting) 24 25 DANIEL CLAUW, M.D. 26 (Center for Devices and Radiologic Health) 27 Professor 28 University of Michigan 29 Chronic Pain & Fatigue Research Program 30 24 Frank Lloyd Wright Drive 31 Ann Arbor, Michigan 48106 32 33 34 ACTING INDUSTRY REPRESENTATIVE: (Non-voting) 35 36 FRED LASKY, PH.D. 37 Director, Regulatory Affairs 38 Genzyme Diagnostics 39 1 Kendall Square 40 Cambridge, Massachusetts 02139-1562 1 7 2 1 ATTENDEES (Continued) 2 3 GUEST SPEAKERS: (Non-voting) 4 5 LESLIE CROFFORD, M.D. 6 Associate Professor of Internal Medicine 7 University of Michigan 8 Division of Rheumatology 9 5510 MSRB-1 10 Ann Arbor, Michigan 48109 11 12 GEORGE WELLS, M.S.C., PH.D. 13 Chair and Professor 14 Department of Epidemiology and 15 Community Medicine 16 University of Ottawa 17 Ontario, Canada K1H 8M5 18 19 20 PATIENT REPRESENTATIVE: (Voting) 21 22 Lynne Kennedy Matallana, M.S., B.A. 23 National Fibromyalgia Association 24 Orange, California 25 26 27 FOOD AND DRUG ADMINISTRATION STAFF: 28 29 MARIA LOURDES-VILLALBA, M.D. 30 LEE SIMON, M.D. 31 JAMES WITTER, M.D., PH.D. 32 33 34 ALSO PRESENT: 35 36 VIBEKE STRAND, M.D., FACP 1 8 2 1 C O N T E N T S 2 3 AGENDA ITEM PAGE 4 5 CONFLICT OF INTEREST STATEMENT 6 by Ms. Johanna Clifford 9 7 8 OPENING REMARKS 9 by Dr. James Witter 11 10 11 HISTORICAL BACKGROUND OF FIBROMYALGIA 12 Pre-ACR Diagnostic Criteria 13 by Dr. Laurence Bradley 31 14 15 Basic Mechanisms 16 by Dr. Leslie Crofford 58 17 18 Post-ACR Diagnostic Criteria 19 by Dr. Daniel Clauw 86 20 21 A Patient's Perspective 22 by Ms. Lynne Matallana 129 23 24 Outcomes: Multi-System Impact 25 by Dr. George Wells 138 26 27 OPEN PUBLIC HEARING 159 28 29 CHARGE TO THE COMMITTEE 30 by Dr. Lee Simon 159 31 32 COMMITTEE DISCUSSION AND RESPONSE TO FDA QUESTIONS 177 1 9 2 1 P R O C E E D I N G S2 (8:05 a.m.)3 DR. FIRESTEIN: Thank you very much, and 4 welcome to everybody, to this meeting of the Arthritis 5 Advisory Committee.6 I'm Gary Firestein, currently the Chair, and 7 we have a number of new people sitting at the table. So I8 think the first thing that we ought to do is go around the9 table and introduce everybody. Why don't we start with 10 our august leader?11 DR. SIMON: Hi. Good morning. I'm Lee Simon.12 I'm the Division Director of Analgesic, Anti-inflammatory 13 and Ophthalmologic Drug Products, and a rheumatologist.14 DR. WITTER: Good morning. Jim Witter, waking15 up here, clinical team leader in 550.16 DR. ABRAMSON: Steve Abramson, rheumatologist,17 NYU and Hospital for Joint Diseases.18 DR. GIBOFSKY: Allan Gibofsky, rheumatologist,19 Hospital for Special Surgery, Cornell.20 DR. WILLIAMS: Jim Williams, rheumatologist, 21 University of Utah.22 MS. McBRAIR: Wendy McBrair, Director of 1 10 2 1 Arthritis Services, Virtua Health, in New Jersey, consumer2 rep.3 DR. HOFFMAN: Gary Hoffman, rheumatologist, 4 Cleveland Clinic.5 DR. BRADLEY: Larry Bradley, psychologist, 6 Division of Rheumatology, University of Alabama at 7 Birmingham.8 MS. CLIFFORD: Johanna Clifford, Food and Drug9 Administration, Executive Secretary to this meeting.10 DR. KATZ: Nathaniel Katz, a neurologist in 11 Boston, Massachusetts.12 MS. MATALLANA: Lynne Matallana, patient 13 representative, Founder and President of the National 14 Fibromyalgia Association.15 DR. FINLEY: Michael Finley, rheumatologist, 16 Western University.17 DR. ANDERSON: Jennifer Anderson, 18 statistician, Boston University.19 DR. CUSH: Jack Cush, rheumatologist, 20 Presbyterian Hospital, Dallas.21 DR. STAUD: Roland Staud, rheumatologist, 22 University of Florida. 1 11 2 1 DR. TURK: Dennis Turk, psychologist, 2 University of Washington.3 DR. LASKY: Fred Lasky, Director of Regulatory4 Affairs, Genzyme, industry representative.5 DR. FIRESTEIN: Thank you very much.6 And before we get started, one minor change in7 the schedule. Because there were no requests for 8 presenting at the open public hearing, that is going to be9 canceled, and Dr. Simon's charge to committee will replace10 that at 11:30.11 So why don't we go ahead and get started with 12 the "Conflict of Interest Statement" from Ms. Clifford.13 MS. CLIFFORD: The following announcement 14 addresses conflict of interest issues with respect to this15 meeting and is made a part of the record to preclude even 16 the appearance of impropriety at this meeting.17 The topics to be discussed today will not 18 focus on any particular product or company but rather may 19 affect those companies developing and studying products 20 for treatment of fibromyalgia. The conflict of interest 21 statutes prohibit special government employees from 22 participating in matters that could affect their own or 1 12 2 1 their employer's financial interests. All participants 2 have been screened for interests in the products and 3 companies that could be affected by today's discussions.4 In accordance with 18 United States Code, 5 section 208(b)(3), the Food and Drug Administration has 6 granted waivers for the following individuals, because the7 agency has determined that the need for their services 8 outweighs the potential for conflict of interest. They 9 include Gary Firestein, Dr. Gary Hoffman, Dr. Steven 10 Abramson, Dr. Allan Gibofsky, Dr. Dennis Turk, Dr. 11 Nathaniel Katz, and Dr. Laurence Bradley.12 In addition, Dr. Daniel Clauw has been granted13 a limited waiver that permits him to give his presentation14 on "Post-ACR Diagnostic Criteria" and to answer questions 15 directly related to his presentation. Dr. Clauw is 16 excluded from participating in the remainder of the 17 committee's discussion.18 A copy of the waiver statements may be 19 obtained by submitting a written request to the agency's 20 Freedom of Information Act Office, room 12A-30 in the 21 Parklawn Building.22 With respect to FDA's invited guests, there 1 13 2 1 are reported interests that we believe should be made 2 public to allow the participants to objectively evaluate 3 their comments.4 Dr. Leslie Crofford has been involved in 5 studies of Pfizer's pregabalin and Eli Lilly's duloxetine.6 She consults for Pfizer and Wyeth and previously consulted7 with Cypress. Dr. Crofford also receives speaker fees and8 is a scientific advisory for Pfizer.9 Dr. Fred Lasky is participating as a non-10 voting industry representative, acting on behalf of 11 regulated industry. Dr. Lasky is a full-time employee of 12 Genzyme and has a sales relationship with Wyeth. He would13 like to disclose that he owns a nominal amount of stock in14 Johnson & Johnson.15 In the event the discussions involve products 16 or firms not on the agenda for which a FDA participant has17 a financial interest, the participants are aware of the 18 need to exclude themselves from such involvement and their19 exclusion will be noted for the record.20 With respect to all other participants, we ask21 in the interest of fairness that they address any current 22 or previous financial involvement with any firm whose 1 14 2 1 products they may wish to comment upon.2 DR. FIRESTEIN: Thank you very much.3 The first item on the agenda is from Dr. 4 Witter, who's going to make some opening remarks.5 DR. WITTER: Good morning.6 We arranged for some sun for you today. We 7 haven't had that around here a lot, so please enjoy it in 8 here.9 We have an interesting day, I think, set up. 10 This has a potential to be an historic day. We're going 11 to be discussing something today that we have not at this 12 point really discussed in any great detail at an advisory 13 committee meeting, and we have a task today, which is 14 essentially to go about and have a discussion about 15 creating a claim for fibromyalgia. So I'm sure we'll find16 it interesting, and some folks would hope that at the next17 meeting, we are actually talking about approving something18 for fibromyalgia. Time will tell.19 So we have several goals for the meeting. I'd20 like to just review those for today. One of those is 21 essentially to gather input then regarding the development22 and approval for drugs that treat fibromyalgia. This 1 15 2 1 discussion will help us and will enrich the analgesic 2 guidance process in rewriting the document. I think most 3 of you know that we are in the process of revising the 4 1992 guidance documents. So this will be an informative 5 meeting in that regard as well.6 We hope to address what we've come to 7 understand is an important public health issue. Estimates8 are, depending on where you read, it affects anywhere from9 4 to 10 million people in the United States alone, and we 10 hope that this discussion will also help us to better 11 understand how fibromyalgia represents a "model" of 12 chronic pain. I'll be discussing a bit later what we mean13 by the term "model".14 So we talk about claims and labels. Let's 15 make sure that we are on the same page. It's stated quite16 often that although label claims have legal and regulatory17 uses, their central purpose is to inform health care 18 providers and patients about the documented, and I stress 19 documented, benefits and risks associated with a product. 20 So claims, therefore, describe clinical benefits and 21 that's really what we're going to be trying to address 22 today. What are those clinical benefits? The better that 1 16 2 1 a product is labeled, the more effective it is then to 2 allow for a useful risk management program which is 3 something that we're all very much concerned about these 4 days.5 So fibromyalgia. What is it? Well, if you 6 look at the Arthritis Foundation's web page, you'll find 7 some of the following. They describe it as an arthritis-8 related condition, characterized by generalized muscular 9 pain and fatigue. I'd like to stress the word "and". 10 It's described as a condition, referred to really as a 11 syndrome, because it is a set of signs and symptoms that 12 occur together. It's confusing. It's often misunderstood13 and a lot of people, including health care providers, 14 maybe don't even believe that it exists. Part of the 15 problem is that it has very common symptoms with no 16 specific laboratory criteria.17 How does the American College of Rheumatology 18 classify fibromyalgia? I know that that'll be a big part 19 of our discussion today. Well, there are really two 20 criteria that need to be satisfied. One is that you have 21 a history of chronic, in this case defined as 3 months, 22 widespread pain. The pain needs to be on the left side 1 17 2 1 and the right side. It needs to be both above and below 2 the waist. It needs to involve the axial skeleton, and 3 then you have to have pain when you digitally palpate in 4 11 of 18 tender spots. This palpation has to be with the 5 force of 4 kilograms and this has to be described as pain,6 not tenderness. So what we'll be discussing today, I'm 7 sure, is whether or not this is a viable and workable 8 inclusion criteria for some of the clinical trials that 9 will be coming.10 Well, how do we treat fibromyalgia? Again 11 turning to the Arthritis Foundation's web page, there are 12 a variety of strategies. One important one is education, 13 so that patients can understand and hopefully better 14 manage what this condition is or isn't. Relaxation 15 techniques, which are intended to ease tension and 16 anxiety. Various forms of exercise to increase one's 17 flexibility and cardiovascular fitness, and then certain 18 drugs, which are intended to decrease pain and improve 19 sleep, and again I stress the word "and".20 There are some interesting drugs here, anti-21 depressants, such as tricyclics and select serotonin 22 receptor inhibitors, and benzodiazepines. What is not on 1 18 2 1 this list that's interesting are things like NSAIDs and 2 Cox-2s and opioids. It may be telling us something about 3 this disease in particular.4 So I'd like to just take a few minutes and 5 kind of get us all on the same page, so to speak, as to 6 how it is that we came to be having this particular 7 meeting today, and I think that there were two meetings 8 that occurred last year that were particularly 9 informative. One of those was the NIH-FDA workshop that 10 occurred in March of 2002. I'll be describing this, in a 11 bit, more. But one of the important features of this 12 meeting was that we came to an agreement at this meeting 13 that chronic pain is in fact an important unmet medical 14 need and needs to be addressed, and during that 15 discussion, we had a breakout session with Dr. Clauw 16 looking at fibromyalgia as an example of chronic pain.17 A few months later, we had an Arthritis 18 Advisory Committee meeting -- and I believe it was in this19 room -- that really was focusing on pain. We talked about20 a variety of claims for marketing for analgesics. I will 21 describe that in a bit, and I'd just like to point out 22 that all of this information is available from our 1 19 2 1 committee meetings on our website. There's just a 2 tremendous amount of information available on the websites3 in general at FDA.4 Speaking of pages, I'd like to point out about5 eight of those. This is a recent publication that just 6 came out. It's entitled "NIH-FDA Analgesic Drug 7 Development Workshop: Translating Scientific Advances 8 into Improved Pain Relief." This is a fairly complete 9 summary of that meeting back in 2002. So if you haven't 10 had a chance to look at it yet, please do so. It's worth 11 the time.12 At that meeting then, we, as I indicated, 13 discussed about chronic pain, and we had a discussion 14 about looking for new models, and again I'll describe 15 models, what I mean by that term, in just a second, but we16 thought it was important at this meeting to get better 17 models so that we could understand some of the important 18 clinical aspects of chronic pain, certainly part of what 19 we'll be discussing today, and if we could also then 20 better understand the chronic pain mechanisms which may 21 serve as treatment targets down the road, this would 22 hopefully allow the design of better clinical trials and, 1 20 2 1 in the long run, hopefully ultimately improve the 2 treatment of chronic pain which is the goal.3 Now, as I've alluded to twice already, we 4 talked about models of chronic pain at this meeting, and 5 what we mean by a model is really a setting that's adapted6 to a clinical trial to understand one of the conditions 7 listed here, for example. It's not necessarily the same 8 kind of thing that you have in clinical practice. In 9 fact, it may be quite different, but it allows us to make 10 certain kinds of decisions from a regulatory perspective. 11 So we looked at osteoarthritis, chronic mechanical lower 12 back pain, diabetic neuropathy, cancer pain, fibromyalgia,13 AIDS, and temporomandibular disease as potential models of14 chronic pain.15 We also discussed at that meeting what should 16 be some of the clinical outcomes that should be studied in17 any particular chronic pain situation. Pain, of course, 18 was first on the list, not surprisingly. We also talked 19 about the use of the patient global, health-related 20 quality of life. Those that are specific to the disease 21 itself were considered to be better, as well as we talked 22 about physical function, again anything that is specific 1 21 2 1 for the disease was felt to be better than if it was just 2 a general questionnaire. We talked about the use of 3 rescue medications, interesting economic considerations 4 which we don't usually get into at FDA, and also how to 5 position adverse events as an outcome measure.6 Now, a few months later then at the July 7 Arthritis Advisory Committee, we talked about pain and we 8 had an interesting two-day discussion about various types 9 of claims that we might be granting for pain in general, 10 and we broke this up into really two categories. First, 11 clinical claims. So we talked about a claim for acute 12 pain and those of you that were there will recall our 13 discussion of the ABCs of acute pain which we won't 14 describe today, but they are at the website. We also 15 talked about chronic pain which will be, again, the focus 16 for today, and the potential for mechanistic claims, that 17 this might be a way to facilitate bridging studies and 18 also a way to push the field forward in the sense of 19 understanding what mechanisms may be. So, for example, 20 for fibromyalgia, one might envision, just as a for 21 instance, a claim to prevent autonomic dysfunction as an 22 example, and that's the discussion that we had at that 1 22 2 1 point in time.2 We wrestled with the idea, as we often do, 3 about what is a minimally clinically-important difference 4 in pain relief. We talked about a responder approach in 5 analgesia, which we'll be describing again today, and we 6 talked about the need to revise the analgesic guidance 7 document.8 So at the meeting, we specifically talked 9 about claim structures. We talked about a variety of ways10 to approach this. One of the first things we talked about11 was to continue to grant, which we've been doing to a 12 certain extent, a claim for general pain, and this 13 affectionately became known as the "six pack" for those of14 you that were there, and what it really described was a 15 situation where any particular analgesic should really 16 treat a variety of pain conditions from a variety of 17 mechanistic situations. So, for example, anything that 18 would be given and granted this general claim would treat 19 something, for example, like osteoarthritis, fibromyalgia,20 and cancer pain, trying to get at a broad swath of 21 mechanisms and etiologies for chronic pain. This was 22 thought to be too high of a hurdle as the discussion went 1 23 2 1 on.2 We then had a limited discussion about the 3 possibility for a more limited claim, for example, 4 something that might treat all musculoskeletal pain. So, 5 for example, this would be a combination of something that6 treats osteoarthritis, fibromyalgia, and chronic lower 7 back pain. But as the discussion continued at that point 8 in time, it seemed the best as we thought through what we 9 had heard that we should continue to push forward with 10 what we've been doing, which is really granting claims for11 specific diseases. You know about osteoarthritis, today's12 discussion being fibromyalgia and chronic lower back pain.13 So that's the current tactic and again that's another 14 reason for today's meeting.15 So this is all history. Today, we need to 16 push forward, and so the charge and the challenge for 17 today is in how do we structure a claim. We now know what18 a claim is. It's a clinical benefit. So how should we 19 approach it? There are fundamentally two different ways. 20 One would be to approach fibromyalgia as a symptom or 21 cluster of symptoms, as is indicated on the Arthritis 22 Foundation web page, for example. Another way, which may 1 24 2 1 be more useful, is to consider fibromyalgia as a complex 2 disease state with varying clinical presentations, and 3 I'll be describing both of those briefly.4 So taking a symptoms approach, we could then 5 look at a pain outcome. Again, this is an obvious and 6 necessary outcome, but I think we need to think it through7 in more of a deeper fashion. For example, we don't want 8 to get into the situation of overpowering clinical trials 9 to drive meaningless endpoints, clinical endpoints that 10 may be statistically important but have no clinical 11 relevance.12 We also should be considering the use of the 13 patient global outcome. As we've been thinking this 14 through in the division, what we are after for this 15 particular outcome is something that is not another look 16 at efficacy. It's not really another look at safety. 17 It's that something in between, that gray zone in between.18 And we maybe then should be discussing the 19 inclusion of a physical function or a health-related 20 quality of life outcome. This seems to make sense because21 these are quite often adversely impacted by pain, 22 particularly chronic pain, and analgesics should improve 1 25 2 1 this or at least they certainly should not worsen it.2 I think it's safe to say that it's the feeling3 of the division that a combination of these really allows 4 us, we feel, to get a better and improved assessment of 5 the patient's experience with the analgesic which is a key6 feature of what we're after and will be the discussion 7 today.8 Well, what about if we take a disease approach9 to fibromyalgia? There has been a lot of discussion that 10 fibromyalgia represents, and in fact it was at the NIH-FDA11 meeting, a chronic pain state. It's a centrally-mediated 12 process. So if we look at fibromyalgia as a chronic pain 13 state, like we do chronic diseases, in chronic diseases, 14 we're comfortable in thinking through treating the 15 disease, curing the disease, even potentially preventing 16 the disease. So should we be taking that same kind of 17 mentality here with fibromyalgia, and would that be useful?18 So as we then have positioned, as is on this 19 cartoon, pain as the central player, is it more useful 20 then to think this through, that pain causes, for example,21 sleep disturbances and pain can cause fatigue, can 22 diminish your quality of life, can lead to cognitive 1 26 2 1 difficulties, and can lead to dysfunction, either 2 autonomic or some kind of loss of functional ability and 3 that may then be all a result of the pain? So, really, we4 need to address the pain, but it's not sufficient.5 So as we take a step back then from the 6 hypothetical and deal with the challenge today then, in 7 either fibromyalgia or chronic pain, what really is 8 important to the patient? I think we need to keep that as9 a focus for our discussion today. There's a large effort 10 underway at FDA, as well as outside, for something that 11 has become to be known as the PRO, or patient reported 12 outcomes, and in fact, there's a draft guidance that 13 should be coming out before the end of the year from us.14 So what are PROs? They are essentially a 15 patient report of a health condition or treatment. They 16 are scientific, patient-centered measures that can 17 evaluate change in health outcomes. They are handled much18 like other outcomes for both drug approval and promotion, 19 which I think is a very interesting aspect to think 20 through today, and their selection, their development, and21 their validation have issues very similar to any other 22 clinical measure, and in particular for pain-related 1 27 2 1 outcomes, we need to then think through psychosocial and 2 all the various other aspects that can be impacted.3 Well, what are some of the ideal 4 characteristics for a metric in, for example, pain? It 5 should, of course, be understandable to patients and 6 clinicians. We all know that pain is the fifth vital sign7 nowadays, and so it seems to make sense that as we 8 transition from the information that we gather in a 9 clinical trial and try and write that into a product 10 label, we should be doing as much as we can to make that a11 seamless transition, so that one understands what was 12 studied in the clinical trial when you look through the 13 label.14 It should also be applicable across various 15 studies to allow across-trial comparisons. One of the 16 reasons a lot of people feel that pain, particularly 17 chronic pain, hasn't moved forward in a more rapid fashion18 is because you can't do rigorous and robust meta-analyses 19 because the outcomes just don't allow it, and so we should20 be thinking forward in that regard to prevent that 21 situation in the future. It should, as I've been 22 describing, detect a clinically-meaningful result. The 1 28 2 1 metric should be responsive to differences in analgesia, 2 and, of course, it should be valid.3 So I'd just like to take a second and talk 4 about a highly-valid index that we utilize in the division5 for WOMAC, in particular the WOMAC pain index subscale, 6 and WOMAC stands, for those of you that may not remember, 7 the Western Ontario and McMaster Universities. I still 8 don't know how they get MAC out of that. But what it 9 really is is a combination of five questions, and as you 10 read through the questions, these are not simple questions11 about pain. They have in them, as you can see, a 12 functional component, at least some of the questions. So,13 for example, walking on a flat surface, pain going up or 14 down stairs, pain at night while in bed, sitting or lying 15 or standing upright.16 These questions are really intended to get at 17 the overall pain experienced in OA. As those of us that 18 take care of patients know, the pain of OA has many 19 different faces, and so I think these questions really do 20 a fairly good job of looking at all of these various 21 situations as we study them in osteoarthritis.22 And as is on this slide then, we do grant for 1 29 2 1 osteoarthritis, for the treatment of signs and symptoms 2 claim, something that has to be based upon -- we've become3 comfortable with utilizing three co-primary endpoints of 4 pain, function, and global in a trial that is 3 months in 5 length. So the WOMAC pain subscale, for example, is quite6 often utilized for the pain component.7 So then as we think through fibromyalgia and 8 consider some of what needs to be thought through, 9 whatever the outcome may be, some of the important points 10 are as follows. For example, as we just discussed with 11 the pain, should this be a single question or is it better12 to come through with a composite question to get a more 13 robust assessment of the outcome? Of course, it has to be14 both statistically and clinically meaningful.15 We have to think through who is included and 16 excluded from the trials because it has an impact on the 17 labeling and the generalizability once this is released.18 We need to think through whether a landmark 19 analysis, meaning at the end of the trial as compared to 20 the beginning, is the better way to go, or should we be 21 thinking through a time-weighted approach, trying to get 22 more of a feel for what happens during the entire trial, 1 30 2 1 not just at the end?2 We need to think through about the issue of 3 daily, in this case I've written here, pain, whether it 4 should be on a daily basis or on a weekly basis. There 5 are pluses and minuses for both. There's a lot of effort 6 nowadays in looking at diaries, particularly electronic 7 diaries, as that may be better to capture the moment pain.8 That appears to be important for fibromyalgia.9 We need to discuss the length of the clinical 10 trials. Is 3 months enough? Is 6 months better? And 11 then, we're going to be wrestling, I'm sure today, with 12 the issue of superiority to placebo, and do we need to 13 continue to follow that paradigm?14 So another way to look through and consider 15 how we might fashion a label and get at a response in 16 fibromyalgia would be to look at the responder approach. 17 As I said, we've discussed this at other venues. It has 18 some potential advantages to it. One of those is that it 19 can allow the outcomes of interest to really be explored 20 and studied in the same patient which can be highly 21 useful. It may lessen or eliminate data imputation which 22 is always a problem, as we're all aware. It allows a 1 31 2 1 certain flexibility in design to capture different aspects2 of the condition, and it's something that is widely 3 utilized in rheumatoid arthritis. We've become very 4 comfortable with it.5 So I thought I'd just take a moment to refresh6 our memories as to what the ACR 20 responder index is. 7 ACR again stands for the American College of Rheumatology.8 The 20 stands for 20 percent improvement. So it comes 9 also as a 50 and 70 percent variety.10 There are two components to this index. One 11 is a required component where you have to have in this 12 case a 20 percent improvement in swollen and tender 13 joints. In addition, you have to have a 20 percent 14 improvement in three of the five following: patient and 15 physician global, patient pain score, a modified health 16 assessment questionnaire, and acute phase reactant. In 17 this case, I've written here C-reactive protein or 18 sedimentation rate.19 So is this useful, this particular responder 20 approach, in terms of fibromyalgia, and if it is, how 21 could we fashion a particular responder endpoint? I've 22 put in this slide a "for instance." This is not at all 1 32 2 1 intended to say that this is what we would like to do. 2 This is just a for instance.3 So we could envision that pain would be the 4 required outcome, again makes sense.5 And then we have other important outcomes that6 I think we need to be considering, as we've been 7 discussing: qualify of life outcome, either a general or 8 a specific; a function or, in this case I've written, a 9 dysfunction outcome; looking at sleep disturbance, 10 fatigue, cognitive impairment as outcomes; and then 11 patient global.12 Would it be then, for example, that we would 13 say that someone is a responder if they have achieved four14 of the important outcomes, plus pain, and then should we 15 be also thinking through that we want to have this in a 16 tiered structure like we do with the ACR 20/50/70? Would 17 that be useful for this condition?18 I'd like to just take a minute and close out 19 here by bringing everybody up to speed on a process that 20 is ongoing. It's called the IMMPACT process. The acronym21 stands for Initiative in Metrics and Measurements in 22 Analgesic Clinical Trials. This is an international 1 33 2 1 organization which has really been devoting itself 2 recently to looking at chronic pain, and in fact, there is3 a publication which has been submitted entitled Selecting 4 Core Outcome Domains in Chronic Pain Clinical Trials.5 It's interesting to look at the six 6 recommendations from this group, being as I've listed 7 here, pain, physical functioning, emotional functioning, 8 patient global, negative health states, and patient 9 disposition, as being representative and overlapping, in 10 fact, what we've been discussing at other meetings.11 So when all is said and done and when we're 12 finally writing a label, we need to remember that the 13 label is, as I've been trying to stress here, the end 14 product of all these efforts. It's the end result of all 15 the randomized, controlled trials and everything that's 16 gone into their thinking.17 So what should the label mean? To the health 18 care provider, for example, the label needs to be 19 describing for this person who can take it, and what type 20 of risk management should be involved in thinking through 21 any particular issues, and importantly, what should it 22 mean to the patient. What can they expect in terms of 1 34 2 1 relief of pain? What can they expect in terms of relief 2 of associated symptoms? And what is the duration of this 3 relief and the degree of this relief? All important 4 issues we need to think through today.5 This is from the latest issue of a magazine 6 entitled Fibromyalgia Aware. It's reminding us that 7 fibromyalgia does not just involve women, but let's hope 8 that today's discussion will lead to a future where more 9 patients look like this gentleman than less that have 10 fibromyalgia.11 And I'd like to close with something that was 12 also the close of the second meeting of the IMMPACT 13 process, which I think is an important reminder for us as 14 well today and that I think I've been stressing throughout15 here, is that it's important really to think about the 16 patient, to assess the patient, and not just the pain.17 So thank you very much.18 (Applause.)19 DR. FIRESTEIN: We have a minute or two for 20 questions from the committee.21 Yes, Dr. Cush?22 DR. CUSH: Jim, that was a good overview. 1 35 2 1 Do you think, though, that we can as an 2 advisory body make recommendations on outcome measures or 3 composite outcome measures when clearly there are none 4 that have been tested or validated and whatnot? So we 5 could throw it out there, but how useful is that to the 6 agency without any sort of testing or confirmation of its 7 value?8 DR. WITTER: I think you've hit on really the 9 core of the problem, that we need to bring that discussion10 forward, and then I think all of us wrestle whether or not11 we can actually do this. If things are not validated in 12 the other areas, can we be pushing forward without those 13 kind of indices like we've had, for example, with 14 rheumatoid arthritis, with osteoarthritis? What do we do?15 So I think you've hit on the head. That really is what we16 need to be discussing today.17 DR. FIRESTEIN: One of the advantages that we 18 had in those other indications is that there were 19 effective agents that could be then used to validate the 20 endpoints, and do you have some notion in terms of how one21 is going to be able to validate an endpoint when there are22 no truly effective agents? 1 36 2 1 DR. WITTER: Well, yes, but I'd prefer to hear2 your discussion later.3 DR. FIRESTEIN: Okay.4 Lee?5 DR. SIMON: Well, isn't this always the 6 dilemma, Jack? The reality is, is that, what came first, 7 the chicken or the egg, and without a discussion that's 8 public and with the experts to determine what may be 9 useful things to look at and what is this real process, 10 based on whatever science exists, then the ability to 11 validate the outcomes in the context of applying potential12 therapies becomes very difficult until we have that 13 discussion, the fundamental beginning step-off to 14 understand what we as some experienced clinicians believe 15 might be a useful way to approach the particular 16 conundrum. So that's really the reason. Although we 17 don't have good validation of the outcomes, we don't have 18 great therapies to date, we do have to make that leap to 19 be able to begin to target what we believe, based on the 20 science, will be useful, and then hopefully people will 21 respond by coming in with potential therapeutics that will22 actually then allow us to test and validate the outcomes. 1 37 2 1 DR. FIRESTEIN: Thanks very much.2 The next presentation on Pre-ACR Diagnostic 3 Criteria will be given by Dr. Bradley.4 DR. BRADLEY: Thank you very much.5 I'm going to fumble here, the requisite 6 fumbling at the podium, while I get my presentation up.7 I want to thank you very much for inviting me 8 here today, and I am going to try today to provide 9 something of a historical perspective on the way we think 10 about fibromyalgia, but really the primary points that I'm11 going to try to make today are that, one, the abnormal 12 processing of sensory information in fibromyalgia is 13 something that is identifiable, it's been reliably 14 observed among different investigators and different 15 clinicians, and this abnormal processing or abnormal 16 sensitivity to pain is something that's not, at least from17 the data we have so far, highly affected by psychosocial 18 factors. However, what people say about their pain, how 19 they report their pain, how they behave in response to 20 pain or their pain behavior is highly modifiable by 21 psychosocial factors.22 Then, I'll also try to conclude by some 1 38 2 1 speculations regarding what types of changes might we 2 expect from compounds that are in development or about to 3 be tested for chronic pain conditions, such as 4 fibromyalgia.5 First of all, as you've already seen from Dr. 6 Witter, fibromyalgia is characterized by several symptoms 7 and the primary characteristics of fibromyalgia include 8 widespread generalized pain and abnormal pain sensitivity 9 evoked by low-intensity stimuli that really vary in 10 nature. These include pressure stimulation, heat 11 stimulation, cold stimulation and so on. And all the 12 criteria that have been developed over the years have 13 really focused on those two primary characteristics.14 In addition, just as Dr. Witter mentioned, there's a 15 variety of other symptoms that occur with fibromyalgia, 16 such as headache, fatigue, sleep disturbance, and a number17 of other symptoms, too.18 Now, there are also alterations in behavior, 19 so that fibromyalgia symptoms are associated with 20 behavioral disturbances and activity levels, social 21 interaction, functional ability, avoidance of events that 22 evoke pain, affective distress and relatively high usage 1 39 2 1 of the health care system.2 Historically, these abnormalities and pain 3 sensitivity, difficulties in function and affect, in the 4 absence of reliable biological markers, have led 5 investigators to take different types of research and 6 clinical pathways. For many years, I think there was sort7 of a dichotomy between those investigators who were 8 searching for a single source of symptoms versus people 9 who tended to attribute fibromyalgia to psychiatric 10 illness or other psychosocial factors.11 When we see the different types of labels that12 have been applied to people who show abnormal pain 13 sensitivity and widespread pain -- and these are labels 14 ranging from DaCosta syndrome and shell shock, all the way15 to fibrositis and affective spectrum disorder -- you see 16 that most of these diagnostic labels have either focused 17 on sort of biological factors, such as concussive effects 18 on the brain, nerve dysfunction, viral illnesses, or they 19 have focused primarily on psychological and psychosocial 20 factors.21 I think in thinking about fibromyalgia now, I 22 think this is truly a disorder where there's abnormal pain 1 40 2 1 sensitivity that's mediated by abnormal processing of 2 sensory input at the spinal and the super-spinal levels, 3 but certainly the way people act with fibromyalgia, what 4 they say about their pain, is influenced by a number of 5 factors.6 The three factors that I think have really 7 helped us better study and understand fibromyalgia are, 8 one, the development of gate control theory back in 1965, 9 work that was done in the 1980s that at least in my mind 10 was really begun by Doug Drossman and the group studying 11 irritable bowel syndrome regarding psychosocial factors 12 that influence health care-seeking behavior, and current 13 work in fibromyalgia specifically beginning in the early 14 1990s by people like Rob Bennett and Jon Russell who began15 to try to identify various biological factors that might 16 be associated with pain and pain sensitivity in people 17 with fibromyalgia.18 With regard to gate control theory, very 19 quickly, the basic tenets are that multiple biological and20 psychosocial factors influence pain perception as well as 21 pain behavior, and therefore, all pain perception and pain22 behavior is determined by this combination of biological 1 41 2 1 and psychosocial factors. So it's really no longer 2 appropriate to identify pain and related symptoms as 3 either organic in nature or functional in nature.4 This slide actually shows Ron Melzack's 5 current version of the gate control theory which he refers6 to as the neuromatrix construct, and essentially what this7 refers to is that the neuromatrix is a construct which is 8 really comprised of a complex set of pathways involving 9 the spinal cord, also various regions of the brain, limbic10 system, somatosensory cortex, thalamus and so on. And the11 function of this neuromatrix is in part genetically 12 influenced, but there's a variety of biological and 13 psychosocial and cognitive factors that can influence the 14 functioning of the neuromatrix which then produces pain 15 perception and pain behavior.16 Now, I'll just show you a few slides showing 17 you sort of the robustness of the sensory processing 18 phenomena that are observed in fibromyalgia. This is a 19 slide from our group in which we compared mechanical 20 pressure pain thresholds at a subset of the ACR tender 21 points in a group of about 20 fibromyalgia patients who 22 did not meet current criteria for major depressive 1 42 2 1 disorder, a group of 10 patients who met criteria for 2 major depressive disorder but did not suffer from 3 generalized pain, and a group of healthy controls without 4 pain, without major depressive disorder. What you see is 5 that the pain threshold levels to pressure stimulation in 6 these fibromyalgia patients is about one-half the level of7 what you see in healthy controls, and at least in our 8 laboratory and I think in most other laboratories, that's 9 a very common finding, that the pain thresholds are about 10 one-half the level in these patients with fibromyalgia. 11 What you see here in these depressed patients, their pain 12 threshold levels are really no different from what you see13 in the healthy controls, and to us, that suggests that 14 depression alone doesn't account for the abnormal pain 15 sensitivity in fibromyalgia. I'll show you some more data16 on this in a bit.17 This is some other data from our laboratory 18 looking at thermal pain thresholds, thermal stimulation 19 applied to the skin, and you see a reliable, significant 20 difference in pain threshold levels where the fibromyalgia21 patients' threshold level is about 5 degrees Centigrade 22 lower than what you see in healthy controls. 1 43 2 1 These are some data actually from Mike Geisser2 and the group at Michigan showing differences between 3 patients with fibromyalgia which you see in this line and 4 healthy controls in magnitude estimates of pain intensity 5 in response to a variety of thermal stimuli, ranging from 6 40 degrees Centigrade to 51 degrees Centigrade, and you 7 see very reliable differences in pain intensity ratings 8 between these two groups.9 Some additional data from Roland Staud who's 10 here. This is a slide from one of Roland's recent studies11 showing greater temporal summation effects in patients 12 with fibromyalgia compared to healthy controls, and 13 regardless of whether the stimuli or the repetitive 14 stimuli are applied with a 3-second or 5-second 15 interstimulus interval, you see much greater evidence of 16 temporal summation in the patients compared to healthy 17 controls.18 So what this shows is that in a variety of 19 laboratories using different techniques, different 20 stimulation, you see very robust and reliable differences 21 in responses to relatively low-intensity stimuli between 22 fibromyalgia patients and healthy controls. 1 44 2 1 Well, let's turn to the question of what we 2 know about psychosocial factors and how that affects pain 3 behavior, including health care-seeking behavior. It's 4 been established in a variety of chronic illnesses that 5 psychological distress or psychiatric illness is 6 associated with greater health care-seeking behavior at 7 tertiary care facilities. In the case of fibromyalgia, 8 there is some evidence that psychological factors are not 9 really necessary or sufficient to produce fibromyalgia 10 symptoms.11 And the person that really, I think, got me at12 least thinking about this and certainly has influenced 13 other investigators, too, is Fred Wolfe who originally 14 came up with this funnel slide which shows that in 15 research studies, we primarily focus on people at tertiary16 care centers, but these people may well be very different 17 from the general population of individuals with 18 fibromyalgia or any other sort of chronic pain disorder.19 We did a study in our laboratory where we 20 examined a group of about -- actually now about 70 21 patients with fibromyalgia and 40 individuals that we 22 recruited from the community who met criteria for 1 45 2 1 fibromyalgia but had not gone to see a doctor for their 2 pain within the past 10 years. We compared these two 3 groups of individuals with regard to a group of healthy 4 controls recruited from the community.5 This particular slide shows the number of 6 lifetime psychiatric diagnoses among these three groups 7 that were determined by the subjects' responses to the 8 diagnostic interview schedule. What you see on this slide9 is that the fibromyalgia patients are actually 10 characterized by a fairly high level of psychiatric 11 morbidity. The patients are characterized by a mean 12 number of 2.5 psychiatric diagnoses over the lifetime 13 compared to our healthy controls who have a mean number of14 diagnoses of 1, and in the case of the healthy controls, 15 these are primarily social phobias and really very minor 16 disturbances. Among our non-patients, actually they show 17 a significantly lower number of lifetime psychiatric 18 diagnoses than the patients but they don't differ from the19 healthy controls in terms of psychiatric morbidity, and as20 you'll see in a moment, the pain sensitivity to pressure 21 stimulation of the non-patients and the patients, is 22 approximately the same. 1 46 2 1 However, when we followed the non-patients 2 over a two-and-a-half-year period, we wanted to see to 3 what extent the non-patients in a sense would convert to 4 patients, how many of those people would become patients 5 over time. What we found, and actually much to our 6 surprise and much to the surprise of our reviewers, is 7 that only 10 of the 40 non-patients actually became 8 patients, sought medical care during that first 2-and-a-9 half years.10 But the factor that best distinguished those 11 who became patients from those who remained non-patients 12 was the number of lifetime psychiatric diagnoses at 13 baseline, and essentially among our non-patients, those 14 who had one or fewer or zero lifetime psychiatric 15 diagnoses had about a 95 percent chance of remaining a 16 non-patient. Those with two lifetime psychiatric 17 diagnoses or greater actually only had about a 50-percent 18 chance of remaining a non-patient. So it was the number 19 of psychiatric diagnoses or psychiatric morbidity that was20 a very great determinant of who became a patient within 21 that 2-and-a-half year period.22 Now, returning back to the baseline data, this 1 47 2 1 slide shows in a separate study where we examined another 2 group of fibromyalgia patients, another group of 3 fibromyalgia non-patients, healthy controls, and we 4 compared these groups on pain threshold levels. What we 5 found is that regardless of whether we were stimulating 6 with pressure stimulation the ACR tender points or a set 7 of control points which were primarily points, such as the8 mid-tibia and the forearm that would involve stimulation 9 of sort of bony skeletal tissue, and regardless of whether10 the patients reported an insidious or a gradual onset to 11 their pain versus a traumatic onset to their pain, we saw 12 approximately the same pain threshold levels in the 13 aggregate among all three groups of individuals with 14 fibromyalgia compared to the healthy controls. And we saw15 that again both at the tender points, as well as at our 16 set of control points.17 So what this suggests is again that regardless18 of psychiatric morbidity, regardless of the nature of the 19 onset of the pain or the factors that people identify as 20 the onset of their pain, you see very similar pressure 21 pain thresholds.22 In our particular study, we also drew cerebral 1 48 2 1 spinal fluid to look at levels of substance P and again 2 you see the same relationship, very similar to what Jon 3 Russell had found in his series of studies. We found that4 among our three groups of people with fibromyalgia, 5 regardless of whether they were patients or non-patients, 6 we found elevated levels of substance P compared to our 7 healthy controls.8 Well, let's turn now and talk about what we 9 know about psychosocial factors and how they affect what 10 people report about their pain. The example that I'm 11 going to use in this next series of slides is reports of 12 stressors, and I think it's pretty well known that 13 patients with fibromyalgia frequently report that their 14 symptoms are intensified by emotional distress or 15 emotional stress or also physical stress.16 Actually there was a study that came out of a 17 couple of years ago from Alex Zautra and the group at 18 Arizona State in which they examined a group of 19 fibromyalgia patients, a group of patients with knee 20 osteoarthritis and healthy controls, and asked each 21 participants to describe a stressful experience in their 22 life over a 30-minute period. What they found was that 1 49 2 1 the fibromyalgia patients at the end of that 30-minute 2 period reported a much greater increase in their clinical 3 symptoms compared to the reports of the patients with knee4 osteoarthritis and also the healthy controls.5 We began a study with Roger Fillingim of the 6 University of Florida, which is still ongoing, where we've7 been looking at the effects of really very brief stressors8 in the laboratory on patients' and controls' responses to 9 thermal stimulation of the skin, and in our particular 10 paradigm, we asked participants to very vividly imagine 11 either a very stressful event from their own life or a 12 relatively neutral or relatively sometimes pleasant event 13 from their own life right before we applied the 14 stimulation.15 And in this particular slide, what I'm going 16 to show you are mean increases in pain unpleasantness 17 ratings among the fibromyalgia patients and the healthy 18 controls at four different levels of thermal stimulation. 19 What this slide shows is actually these bars represent 20 differences in pain unpleasantness ratings in the period 21 following the stressful imagery versus the period 22 following the relatively neutral imagery. What you see is 1 50 2 1 that at 45 degrees, 47 degrees, 49 degrees Centigrade, you2 see substantially greater increases in pain unpleasantness3 among the fibromyalgia patients, very little effect of the4 imagery on pain unpleasantness ratings among the healthy 5 controls. And at 51 degrees -- this is actually a total 6 of about 15 people here -- so again you see no effect 7 among the healthy controls, and due primarily to 1 person,8 you see actually a very large decrease in ratings among 9 fibromyalgia patients. But the primary finding is that at10 these lower levels of stimulus intensity, just thinking 11 about a stressful event over a 4-minute period has a very 12 strong effect on pain unpleasantness ratings.13 Now, when we asked people to give us their 14 ratings of pain intensity, the intensity ratings by both 15 groups are not really strongly affected by thinking about 16 stressful events, but ratings of pain unpleasantness are 17 affected.18 Also, we've been drawing blood and drawing 19 saliva and what we find is, actually with both measures, 20 that our patients with fibromyalgia, about 20 minutes 21 after the stressful imagery, show a relative decrease in 22 cortisol levels compared to the neutral imagery, and we 1 51 2 1 don't see that kind of effect in our healthy controls. So2 there's not enough people yet to look at association 3 between changes in cortisol and changes in pain 4 unpleasantness, but the point is that you do see some 5 evidence of HPA axis dysfunction as a result of the 6 stressful imagery in the fibromyalgia patients compared to7 the healthy controls.8 Well, what do we know about biological factors9 that are associated with pain and distress in people with 10 fibromyalgia? I think there's very interesting work 11 that's going on now regarding both genetic influences on 12 pain and analgesia and also some very good work that's 13 being done using neuroimaging techniques that have 14 documented altered central processing of sensory input in 15 people with fibromyalgia.16 These are data. Actually, these data come 17 from Dan Buskila's group in Israel. Martin Offenbaecher 18 in Munich was the first person to really identify this 19 finding, but both groups, using very different 20 populations, have shown that individuals with fibromyalgia21 -- in Offenbaecher's group, it was primarily women, in 22 Buskila's group, it was all women -- actually a greater 1 52 2 1 proportion of the patients with fibromyalgia compared to 2 controls show a functional polymorphism in the 5-HTT gene 3 promoter region or in the regulatory region of the 5-HTT 4 serotonin transporter gene. And what you see is that 5 there's a greater proportion of patients with fibromyalgia6 who show this short/short allele compared to healthy 7 controls and again that's been found in two separate 8 groups now.9 There's also some work being done on sex-10 related genetic influences on analgesia which may 11 eventually have some impact on fibromyalgia research. 12 This is a slide from a paper that Jeff Mogil and Roland 13 Staud, Roger Fillingim, and a large group of investigators14 recently published showing an interaction between sex and 15 a polymorphism in the melanocortin 1 receptor gene. And 16 what this slide shows is that regardless of whether one is17 using thermal stimulation or ischemic stimulation, that 18 among females having a particular polymorphism, 19 characterized by two variant alleles in this MC1R gene, is20 associated with greater analgesic responses to 21 pentazocine. Among the males, you don't see this sex 22 effect, and I think this is a very interesting line of 1 53 2 1 research, particularly given the fact that fibromyalgia is2 a disorder which affects primarily women.3 What about altered central processing of 4 sensory input? These are some slides from Rick Gracely 5 and Dan Clauw's group at Michigan, and what this shows is 6 that when fibromyalgia patients and healthy controls are 7 exposed to pressure stimulation that varies in intensity 8 but which produces approximately the same report of pain 9 intensity -- and in this case, there was a pain report of 10 about 11 on a 20-point scale -- you see a number of brain 11 regions in which both patients with fibromyalgia and 12 healthy controls show significant activation on fMRI 13 imaging. So by equivalent levels of pain intensity or 14 perceived pain intensity, you see the same brain regions 15 being activated in patients and controls.16 However, when you take the healthy controls 17 and you expose them to the same level of stimulation which18 produced pain in the fibromyalgia patients but which are 19 relatively innocuous to the healthy controls, you 20 primarily see significant levels of activation in a 21 variety of regions in the patients with fibromyalgia. You22 see very little significant activation in the healthy 1 54 2 1 controls2 So the point that these two slides show is 3 that fibromyalgia patients are characterized by 4 augmentation of sensory input which can be identified 5 through neuroimaging of activity in the cerebral 6 hemispheres7 Well, let me conclude the data and sort of 8 summarize the data from this talk. First of all, I think 9 what we've shown is that pain sensitivity, pain-related 10 symptoms, and behavioral disturbances in fibromyalgia are 11 reliably observed by a variety of investigators and can be12 done so by clinicians and this can be done using a variety13 of measurement techniques.14 Pain sensitivity and related symptoms are 15 influenced by biological factors. There's evidence that 16 there may be a genetic predisposition for development of 17 fibromyalgia. That particular serotonin transporter gene 18 or that particular functional polymorphism in that gene is19 also associated with chronic headaches and also some 20 anxiety disorders. So this particular gene might be 21 related to the development of a number of disorders that 22 are part of the fibromyalgia symptom complex. 1 55 2 1 Also, we've seen that abnormal pain 2 sensitivity is associated in our laboratory and in a 3 number of other laboratories with elevated cerebral spinal4 fluid levels of substance P, and also what we will very 5 soon see in the future, I think, is that there's a number 6 of investigators using neuroimaging techniques and I think7 we'll see a number of studies coming along soon which show8 that abnormal pain sensitivity is associated with 9 augmented sensory neural input.10 Now, what we've also seen is that, at least in11 our laboratory, pressure pain sensitivity and CSF levels 12 of substance P really don't vary very greatly as a 13 function of affective illness or lifetime psychiatric 14 morbidity. However, what we do see is that changes in 15 plasma cortisol levels, reports of pain unpleasantness in 16 response to thermal stimulation, and other sorts of pain-17 related behaviors, such as health care-seeking behavior, 18 are associated with variations in psychosocial factors and19 affective disturbance.20 Well, what does this mean for clinical trials?21 I think a number of pharmacologic interventions that are 22 used currently, also the interventions that are being 1 56 2 1 developed for use in fibromyalgia are all compounds that 2 alter activity at the superspinal level. They alter 3 activity in the brain that can influence pain inhibition 4 or to a certain extent alter central processing of neural 5 input. And I think that what we should be able to observe6 in clinical trials is that these compounds should be able 7 to influence ratings of pain intensity, and I think some 8 of the newer compounds that are in preclinical trials, for9 example, some of the new glutamate receptor inhibitors 10 that are in development, may actually also alter abnormal 11 pain sensitivity.12 These interventions, both the current 13 interventions and the interventions that are in 14 development, may also modify pain behaviors through 15 alterations in pain intensity, but also secondary 16 alterations on pain affect, affective disturbance, and 17 other psychosocial factors.18 And while this wasn't really part of what 19 we're talking about today, I do want to mention that I 20 think that the development of effective compounds that may21 alter pain in people with fibromyalgia may also be helpful22 to clinicians who use psychosocial interventions with 1 57 2 1 fibromyalgia patients. When I look at the literature on 2 cognitive-behavioral therapy, other sorts of psychosocial 3 interventions, when you look at the studies that really 4 use adequate attention placebo controls, at least my 5 reading of those studies is that most of them don't 6 produce effects that are much greater than what you see 7 with a good placebo control, and I think one thing that 8 psychosocial investigators have yet to really think much 9 about is why do we see these relatively modest effects 10 with psychosocial interventions compared to what we see in11 patients who are treated by psychosocial interventions, 12 patients who have rheumatoid arthritis, osteoarthritis, 13 irritable bowel syndrome and so on. And I think that one 14 of the factors is that for these other kinds of diseases 15 and disorders, there are relatively effective 16 pharmacologic compounds that influence pain, and I think 17 that so far, we really don't have very good compounds that18 reliably influence pain in fibromyalgia. But I think that19 once these compounds are developed and tested, and if they20 are shown to be effective, I think that they will have a 21 secondary effect in the sense that they will enhance the 22 effectiveness of psychosocial interventions for pain and 1 58 2 1 pain behavior in fibromyalgia.2 So I'll conclude there and thank you very 3 much, and I'll be glad to take any questions you might 4 have.5 (Applause.)6 DR. FIRESTEIN: Thank you.7 Dr. Katz?8 DR. KATZ: Yes. Hi. Thanks. Two quick 9 questions.10 Number one, the distinction that you made 11 between the two subgroups of people with fibromyalgia, the12 patients versus the non-patients, was the clinical 13 expression of the syndrome any different between those two14 groups?15 DR. BRADLEY: Yes, that's a very good 16 question, and even though the pain sensitivity was very 17 similar in the two groups, the non-patients reported 18 significantly lower levels of pain on the McGill Pain 19 Questionnaire compared to the patients. And they also 20 again -- and this is in accord with their difference in 21 psychiatric status -- reported lower levels of depression 22 and anxiety on standardized questionnaires. So the 1 59 2 1 expression of the disorder was different, although the 2 pain sensitivity was the same.3 DR. KATZ: And the second question is, I was 4 interested in your very helpful summary of the studies 5 looking at hyperalgesia to various forms of stimuli and 6 neuroimaging, which are obviously used to suggest that 7 this disease therefore is independent from psychiatric 8 influences.9 But my question is about the control groups 10 used in those studies. Have any of those studies used 11 patients with somatoform pain disorders as the control? 12 That would seem to be the relevant control group here.13 DR. BRADLEY: Yes. To my knowledge, no, and 14 we've not tried to look at that. I don't know of other 15 investigators looking at that right now. I don't know if 16 your group is looking at that at present.17 (Off microphone speaker.)18 DR. FIRESTEIN: I have one quick question. I 19 think the data that you presented on patients versus non-20 patients was fascinating. One of the questions is, if 21 patients don't or if individuals that meet the criteria, 22 in terms of the number of tender points, don't seek 1 60 2 1 medical attention and don't view this necessarily as a 2 medical illness, do we want an indication for treating 3 such individuals, and is it a disease only when the 4 psychiatric manifestations come?5 The corollary of that is whether or not the 6 real full expression of the disease is really related to 7 psychiatric manifestations, and is the perception of pain 8 a self-selecting group of individuals that represent a 9 bell-shaped curve? In other words, do those individuals 10 that meet the criteria because there's a broad spectrum of11 individuals that are tender at 4 kilograms per X number of12 square centimeters but that's within normal human 13 experience?14 DR. BRADLEY: I'm going to try to respond to 15 those two different dimensions of your question and please16 tell me if I'm really responding to the issues.17 I think with regard to the bell-shaped curve, 18 yes, there is a bell-shaped curve in terms of pain 19 sensitivity. I think what's important is that both the 20 patients and non-patients were really on the far side of 21 that bell-shaped curve. I mean, they were way up in that 22 upper 2.5 percent. So those two groups were really 1 61 2 1 equivalent in terms of pain sensitivity and that was 2 really not associated with psychological, psychosocial, 3 psychiatric factors. And we've done that study twice now.4 So at least in our laboratory, that's a very reliable 5 finding.6 I think in my mind, the issue is how people 7 perceive their pain and whether they seek health care for 8 their pain. I think that is very much influenced by the 9 variety of factors, and it's not just psychological or 10 psychiatric factors. I think there's a wide array of 11 socioeconomic, cultural, family learning/history variables12 that influence that type of behavior. So I think the 13 question that you're asking is, is the identification of 14 fibromyalgia sort of a psychosocial phenomenon, and I 15 would say that the perception that one has musculoskeletal16 pain and that one is -- well, and this is the way we 17 really did recruit people for the study, is we put out 18 advertisements in the newspaper and through the television19 media looking for people with persistent, longer-than-6-20 month history of widespread musculoskeletal pain. And 21 when people responded to those advertisements, we then 22 went through sort of a three-step process of screening 1 62 2 1 them.2 We would screen them very briefly over the 3 telephone using Fred Wolfe's questionnaire from 1992, I 4 think one of his papers in '92. If they passed that 5 screen, we would then ask them to send us copies of their 6 recent medical records. In these two studies, we wanted 7 to exclude people who had other kinds of illnesses, 8 diseases, that could cause widespread pain, such as people9 with neuropathies, people with a variety of other 10 problems, back surgeries, neck surgeries, and so on, that 11 could produce the symptoms. So these were really people 12 without other medical causes that we could identify for 13 their pain.14 Then if they passed that screen, then they 15 came into our GCRC and one of my rheumatology colleagues, 16 Graciela Alarcon, would examine and interview each person,17 and we would, to the best that we could, really try to 18 screen out people who had other sorts of medical problems 19 that might account for their pain.20 So most of the non-patients really didn't have21 a label for what they were experiencing, except that they 22 hurt all over, and the non-patients also -- I guess I 1 63 2 1 should mention this, too. If you looked at sort of 2 measures of self-efficacy and coping strategy usage, these3 people were very, very good copers and really most of them4 had an experience at some point longer than 10 years ago 5 when they went to see a doctor for their pain. And these 6 studies were done in the early 1990s. So they would have 7 an experience, the doctor would say, well, I don't know 8 what's causing your pain, and these people would go home 9 and just stop there and take care of themselves.10 So the perception of pain and the pain 11 sensitivity was not influenced by psychological factors. 12 How people responded to the pain certainly was influenced 13 by psychological factors, and actually, again, the non-14 patients were such a robust group in terms of coping, that15 after 2-and-a-half years, again only 10 of them had become16 patients. So I think the pain problem was not a construct17 of their psychological situation, but their behavior 18 certainly was influenced by it.19 DR. FIRESTEIN: Dr. Strand? Oh, I'm sorry. 20 Never mind.21 DR. STAUD: I was wondering if you would like 22 to comment on the striking sex difference in fibromyalgia 1 64 2 1 with the ratio discussed in 8 to 1 or 8 to 2 or 9 to 1 in 2 males versus females and what particularly the 3 psychosocial aspects are that explain most of this, 4 because in the general population, males generally have, 5 on psychophysical testing, lower sensitivities to painful 6 stimuli.7 DR. BRADLEY: That's a phenomenon that's 8 really not well understood. I mean, we all are aware that9 in rheumatic diseases, that there's a tendency for women 10 to be more susceptible to rheumatic diseases than men, but11 the ratio that we see in fibromyalgia is even more 12 striking than what we see in the inflammatory rheumatic 13 diseases.14 I can really only speculate and I think that 15 there must be, for example, factors, and to some extent, 16 we already know that, for example, fluctuations in 17 hormonal status, sex hormone status, among women 18 influences their perceptions of pain.19 So I think that certainly there's probably a 20 combination of genetic and also hormonal factors and 21 perhaps other biological and to some extent perhaps even 22 non-biological factors that account for that sex 1 65 2 1 difference, but it's really striking and it's more 2 striking than what you see in really any other disease or 3 disorder.4 DR. FIRESTEIN: Two more quick questions. Dr.5 Cush and Dr. Turk.6 DR. CUSH: Last year at our pain workshop, we 7 had talked about setting up outcome measures or trying to 8 go towards outcome measures that were not only based on 9 symptomatic control but also mechanisms. So do you think 10 that we're at a point or as we try to formulate some 11 guidelines for trials and outcomes where we can talk 12 beyond symptoms and talk about sort of mechanistic control13 of pain?14 DR. BRADLEY: Well, yes. I think that 15 probably the state of the art is right now -- the problem 16 is not the state of the art of measurement, but I think 17 the problem is sort of the state of the art of where we 18 are in developing compounds for persistent pain. I think 19 right now, we don't have compounds that can be really used20 safely in human beings. For example, the NMDA receptor 21 antagonists really are very problematic for use with 22 humans because they induce sort of hallucinations and all 1 66 2 1 kinds of other problems.2 I think eventually there will be compounds 3 that will influence events more at the dorsal horn level 4 of the spinal cord, and I think at that point, I think 5 it's reasonable to then try to use measures of 6 sensitivity, whether they're biological measures or sort 7 of behavioral measures of sensitivity, as an outcome 8 measure.9 I think for right now, I think it's really 10 interesting to use those measures as sort of secondary 11 outcome measures but without any great expectation that 12 the compounds that we have currently will have a great 13 effect on pain sensitivity, regardless of whether you're 14 looking at that from a behavioral level or from a more 15 neuroimaging or other type of biological level.16 DR. TURK: Thank you for that overview, Larry.17 As you presented your data, other than the 18 insidious onset, traumatic onset, you really tended to 19 look at averages across large groups of patients, and I'm 20 wondering if there's any thoughts you might have on 21 whether there may be subgroups of patients with 22 fibromyalgia based on either physiological factors, on 1 67 2 1 symptom presentations, on sensory sensitivity, 2 psychological factors, because there are several groups 3 that have tried to look at whether there may be 4 differences among those groups. I was interested in your 5 insidious onset, traumatic onset, because there's at 6 least two or three studies that have shown pretty large 7 differences in people with different reports of onset of 8 symptoms. So I wonder if you have any comments about that.9 DR. BRADLEY: Well, I think in regard to the 10 first part of your question, with regard to subgroups, 11 yes, I think that you're right, and I'm glad you brought 12 this point up. Within the patient population, there is 13 really a variation, particularly in terms of psychological14 functioning, actual displays of functional abilities, and 15 I think that it is important to note that patients do 16 vary. There are patients who have relatively low levels 17 of psychological distress, even though on the average you 18 tend to see very, very high levels of distress.19 I think that it's worthwhile looking at those 20 subgroups and regardless of whether one uses techniques 21 like the MPI, for example, which is a very good technique,22 or other types of techniques, it is worthwhile to look at 1 68 2 1 potential interactions between variations in distress or 2 function and response to pharmacologic treatments and 3 responses to behavioral treatments, too.4 I think I've lost the second part of your 5 question. What was the last point you raised?6 DR. TURK: I think you covered it. It was 7 just on the traumatic versus insidious onset.8 DR. BRADLEY: It may have something to do with9 the fact that -- again, we were very careful to screen 10 people, to eliminate people, for example, who had other 11 problems that potentially could produce chronic pain. So,12 for example, we did not take anybody into our studies who 13 had a back surgery or a neck surgery. So there probably 14 was a certain group of people with a certain type of 15 trauma that resulted in surgical intervention who were not16 part of our studies. So factors such as that may account 17 for the relative sort of group or the average level of 18 homogeneity between those groups which I think we're 19 probably much more stringent than other groups have been 20 in the past in looking at that issue.21 DR. FIRESTEIN: Thank you very much for a very22 interesting presentation. 1 69 2 1 Next, Dr. Crofford's going to talk about basic2 mechanisms.3 DR. CROFFORD: Thanks, Gary, and I'd like to 4 thank the FDA. I actually would like to congratulate you 5 on taking on this problem. This is a problem that we've 6 been struggling with in rheumatology for many years, and I7 think that the FDA really ought to receive the credit that8 they deserve for really taking this on. So I'm pleased to9 be here.10 In framing my comments this morning, what I'd 11 like to do is start with some thoughts about actually 12 developing effective treatments for fibromyalgia syndrome,13 and I think from a very incredibly pragmatic standpoint, 14 which is, I think, where we need to start with this 15 condition, the first question is whether or not 16 fibromyalgia syndrome can be clinically recognized and 17 diagnosed using the current ACR criteria because that's 18 where we are.19 I would submit that even though the ACR 20 criteria aren't perfect -- and we can certainly talk about21 them at great detail and you'll probably get a lot of 22 different opinions -- that they actually do identify 1 70 2 1 patients with a predictable symptom profile which is what 2 we want. We want to be able to use the criteria to 3 identify a group of patients that are predictable and have4 the opportunity to respond to certain types of 5 interventions.6 Now, that's not to say that fibromyalgia 7 syndrome patients identified by the ACR criteria don't 8 contain subsets. I think they certainly do contain 9 subsets of patients, but when you apply these ACR criteria10 correctly, you do get a group of patients that are a good 11 subject pool for clinical trials.12 The second point is we need to understand what13 are the critical symptom domains in these patients that 14 must improve for an intervention to be an effective 15 treatment for fibromyalgia syndrome, and one could jump 16 off the excellent presentation of Dr. Witter and think 17 about all kinds of different ways that you could develop 18 criteria that may be important to patients with 19 fibromyalgia syndrome. This is certainly what we're about20 today, and I think certainly there are some thoughts that 21 I'll present later on.22 Thirdly, what mechanisms underlie fibromyalgia 1 71 2 1 syndrome that may allow us to predict the types of 2 treatments that may be effective in fibromyalgia syndrome?3 I think we ought to think about that or at least the 4 pharmaceutical companies ought to think about that as they5 move forward in attempting to predict what types of 6 compounds may be useful in this syndrome, and then, 7 lastly, which I won't address at all but I think Dan Clauw8 will address quite thoroughly and Jim has already talked 9 about it and Dr. Wells as well, how best can we measure 10 improvement in response to treatment?11 So I brought this slide just because I think 12 it's important that we recognize that fibromyalgia 13 syndrome is debilitating, that the patients have an impact14 on their lives for the most part by the presence of these 15 symptoms, whether they seek treatment or not. They answer16 advertisements. So they notice that there's something 17 wrong with them.18 In thinking about the fibromyalgia symptom 19 domains, I think the first thing that we all recognize is 20 that patients have pain. It's required that this pain be 21 widespread and involve the musculoskeletal system. That 22 having been said, patients with fibromyalgia also have 1 72 2 1 other types of pain, including regional musculoskeletal 2 pain syndromes, including temporomandibular disorder, and 3 visceral pain syndromes, and I won't spend any time 4 specifically talking about these things, but pain is one 5 of those things that has to be a given when we think about6 fibromyalgia syndrome and when we think about its 7 management.8 But fibromyalgia patients also have non-pain 9 symptoms, and we've already heard about some of them, and 10 I'll spend the majority of my time talking about the non-11 pain symptoms which include fatigue, sleep disturbance, 12 cognitive dysfunction, depressive and anxiety symptoms 13 which I should be careful to distinguish between diagnosis14 of major depressive disorder. These are not required but 15 they're almost universally present in patients with 16 fibromyalgia syndrome.17 As we heard from Larry, the pain is widespread18 clinical pain, and no mechanism is implied in this 19 definition of widespread clinical pain. However, the ACR 20 tender points have to be present and the tender points 21 measure a domain that incorporates probably both this 22 concept that Dr. Bradley brought up, that there's either 1 73 2 1 hyperalgesia or allodynia in these individuals, but they 2 probably also incorporate non-pain domains or something 3 that we call distress. What I'd like to just bring your 4 attention to, when Larry brings up data that demonstrate 5 that patients with fibromyalgia have an increased noxious 6 threshold for thermal sensitivity, for example, that 7 measures this domain of whatever we want to call allodynia8 or hyperalgesia, but that the tender points probably 9 measure something in addition to this noxious stimulus, 10 and these are data that were very nicely demonstrated by 11 Dan Clauw looking at different paradigms and the 12 comparison between what tender points measure and what the13 kind of more sensitive measures of allodynia actually 14 measure.15 Now, I actually don't think this is a bad 16 thing because I think maybe by happenstance that's what 17 has happened when we developed the tender points, is that 18 for some reason -- and maybe this was just prescience on 19 the part of the committee that developed the tender points20 -- these ACR tender points actually do measure some kind 21 of a combination domain.22 Then the question of whether the pain of 1 74 2 1 fibromyalgia syndrome is real always comes up when you 2 talk to rheumatologists because many rheumatologists don't3 believe that the pain is real, but I think that you've 4 just seen a demonstration from Dr. Bradley that with 5 respect to psychophysical testing, you can demonstrate 6 measurable differences. He didn't present data that 7 evoked potentials which Jurgen Lorenz has used to 8 demonstrate actual differences in central representation 9 of pain inputs, and then he showed data from Dan Clauw and10 Rick Gracely's group demonstrating that the central 11 representation of pain by fMRI actually demonstrates the 12 veracity of the patient's complaint to increased pain.13 So stimulus detection of patients with 14 fibromyalgia is normal. There is an ultranoxious 15 threshold that is multimodality, so that that is something16 that we can point to as a mechanism of pain. As I 17 previously said, the central representation of pain 18 confirms the veracity of the subjective pain complaints. 19 And pain cannot be explained by tissue damage. That 20 having been said, pain generators are very common in 21 fibromyalgia and oftentimes you can improve the overall 22 clinical experience of pain by addressing these pain 1 75 2 1 generators, for example, in patients with rheumatoid 2 arthritis, osteoarthritis, or other types of mechanical 3 problems. Taken together, all of these implicate central 4 factors in fibromyalgia syndrome pain.5 Now, Larry presented all the clinical data, 6 and I'd just like to make some comments about how one 7 might get there. Certainly the data that Roland Staud and8 Don Price and their group have presented as well as data 9 from our own group and Dan Clauw's group suggest that 10 central sensitization, otherwise known as activity-11 dependent plasticity, may be present in these patients. 12 Certainly it's difficult to prove but that's something 13 that's been suggested. Neuronal plasticity in the spinal 14 cord modifies the performance of the nociceptive pathways,15 so that one develops an exaggerated or prolonged response 16 to noxious input, called hyperalgesia, and enables 17 normally innocuous inputs to activate nociceptive 18 pathways, called allodynia.19 These mechanisms are transcription independent20 and dependent and the mediators of this spinal central 21 sensitization would include such things as the excitatory 22 amino acids and their receptors, the NMDA receptors, 1 76 2 1 substance P and other neuropeptides, that are acting 2 through their G protein-coupled receptors. And certainly 3 it's known that in models of pain, that there's increased 4 activity of kinases, such as protein kinase C and many 5 others, that phosphorylate ion channels and receptors and 6 result in neuronal hyperexcitability. So that, at least 7 from animal models, the mechanisms by which this activity-8 dependent plasticity is modulated are known and some of 9 the types of drugs that may work in this type of process 10 could be predicted from these data.11 It's also important to note that there's 12 descending modulation of pain. It's bidirectional, 13 including inhibitory and facilitatory descending control. 14 These pathways that actually modulate the inputs at the 15 dorsal horn are mediated by serotonin and noradrenaline 16 and again this may give us some clues as to why certain 17 drugs may be effective in central pain syndromes and why 18 non-steroidals, for example, are typically not very 19 effective in these syndromes.20 Now, it's clear that injury-induced 21 hyperalgesia is dampened by descending pathways, but it's 22 also clear that cortical and subcortical structures can 1 77 2 1 stimulate these facilitatory pathways. Most of the input 2 is integrated at the level of the peri-aqueductal gray and3 rostral ventral medulla, but the types of inputs that come4 into these systems would include things like vagal 5 afferents, would include things like inputs from the 6 stress axes, that Dr. Bradley nicely described the 7 influence of stress on pain perception, certainly their 8 cortical structures, including the anterior singulate 9 gyrus and many others, whose input is integrated at these 10 levels. And it also should be noted that the dynamic 11 plasticity at the level of the rostral ventral medulla is 12 also mediated by NMDA receptors.13 Just in pictorial representation, the cerebral14 cortex influences this descending bidirectional modulatory15 control through many different mechanisms. Goal-directed 16 behaviors can certainly change the experience of pain. 17 Attention and distraction can change the experience of 18 pain; expectancy, interaction with the limbic system. 19 Subcortical systems would include stress-induced analgesia20 but also hyperalgesia, and mid-brain and brain stem 21 systems integrate signals from the brain and spinal cord. 22 They're the site of opiate action. They're the principal 1 78 2 1 relays of these chemical signals to the spinal cord which 2 again include norepinephrine and serotonin.3 So what are the treatment implications for the4 concept of central pain? The implications would include 5 such things as the treatments that usually are used for 6 normal musculoskeletal pain do not actually work very well7 for most patients with fibromyalgia, and that the 8 treatments must address the problem of this altered pain 9 processing in the spinal cord and potentially alter 10 descending inhibition of pain signals.11 Now, I'd like to move on from pain and talk 12 about the non-pain symptoms and the question of whether or13 not you can attribute these non-pain symptoms to specific 14 mechanisms.15 Non-pain symptoms form something that 16 epidemiologists refer to as a distress cluster which is 17 often associated with multifocal chronic pain. Fatigue 18 itself is actually exceptionally difficult to attribute to19 a specific mechanism, and I think all of us who are 20 rheumatologists, when we think about any of our connective21 tissue disease patients, recognize this.22 The sleep disturbance. I'll talk further 1 79 2 1 about this, but no specific alteration has been described.2 Certainly the disturbances overlap with other conditions 3 that share this distress cluster of symptoms with 4 fibromyalgia syndrome.5 Cognitive dysfunction is present in these 6 patients. There's evidence that cognitive complaints 7 correlate with fMRI differences. I brought this for you, 8 Dr. Turk, to show some data that there are actually 9 differences in the way that patients' brains function 10 under a cognitive load.11 Depression and anxiety are certainly present, 12 and I think Larry nicely pointed out that there's a marked13 increase in the lifetime prevalence, and it is associated 14 with health care-seeking.15 So in terms of fatigue, what does it mean? In16 general, it means decreased energy, need to rest, 17 sleepiness or unrefreshing sleep, struggle to overcome 18 inactivity. From a physical standpoint, it can mean 19 weakness, limb heaviness or post-exertional malaise which 20 is exceptionally common in these patients. On an 21 emotional side, it could be decreased motivation or 22 interest. From a mental or cognitive side, diminished 1 80 2 1 concentration or memory. Functional, difficulty 2 completing daily tasks.3 And you can see by the diversity of what 4 patients actually mean when they say that they're 5 fatigued, that attribution to a specific mechanism really 6 is something beyond what most of us can do. Nevertheless,7 when one thinks about a reduction in fatigue, you can see 8 how a reduction in the perception of fatigue may actually 9 imply improvement across multiple different biological 10 mechanisms.11 Certainly the possible causes of fatigue in 12 fibromyalgia are legion, including the sleep disturbance, 13 depression, anxiety, pain, medications, deconditioning, 14 neurally-mediated hypotension, which may form a subset of 15 some patients, and central mechanisms.16 The one thing that I will say is that fatigue 17 is correlated with many of the other symptoms, and if you 18 actually look at a correlation matrix of fatigue, you can 19 see that the symptom of fatigue is significantly 20 correlated with pain and sleep and actually less so with 21 depression and anxiety, but one can think of it as perhaps22 a marker for many of these other non-pain symptoms. 1 81 2 1 In terms of the sleep disturbances in 2 fibromyalgia syndrome, this is probably understudied and 3 hopefully that's something that will be corrected. The 4 alpha-delta sleep disturbance was first reported by Harvey5 Moldofsky in 1975 and was actually the first biological 6 finding in patients with fibromyalgia. Unfortunately, 7 this alpha-delta sleep abnormality is non-specific. It's 8 certainly not universal and certainly occurs in many other9 types of illnesses and even in normal patients but not 10 nearly to the extent as seen in fibromyalgia and patients 11 with other syndromes.12 It's also been reported that patients with 13 fibromyalgia have reduced slow-wave sleep, that's stage 3-14 4, or delta sleep. It's also not specific, not universal,15 and unfortunately no spectral analyses have actually been 16 reported to examine delta power or even alpha power in 17 patients with fibromyalgia syndrome. Sleep medicine has 18 certainly advanced significantly with new techniques 19 towards spectral analysis and hopefully those will be done20 in the near future.21 The insomnia of fibromyalgia has also been 22 described as psychophysiological insomnia and that's 1 82 2 1 altered sensitivity to extrinsic stimuli. And these are 2 the kinds of things that can actually be measured in a 3 sleep laboratory these days and hopefully will come in the4 near future.5 Now, changing gears to cognitive, I'd like to 6 show this slide, which is always alarming to the audience.7 Most of us fall about halfway down this cognitive slide, 8 but you can see that in most patients, their peak of 9 cognitive prowess occurs at about 20 and we slip and slide10 from there down to where we mostly currently are. This 11 occurs across all domains of cognition actually, with the 12 exception of semantic memory, here measured by vocabulary,13 but that is preserved and perhaps even enhanced and most 14 of us like to think of it as wisdom that makes up for a 15 loss of actual cognitive activity.16 This is a study that we did with Denise Park 17 and Jennifer Glass looking at information processing 18 speed, and one can see that the cognitive problems in 19 patients with fibromyalgia are actually not universal but 20 actually selective in that patients with fibromyalgia 21 syndrome, looking at age-matched controls, have their 22 information processing speed preserved, whereas one can 1 83 2 1 see the predicted reduction in processing speed that one 2 sees in older controls, and in fact, in older controls, 3 it's thought that speed of processing actually explains 4 many of the other elements of cognitive decline.5 But when one looks at fibromyalgia patients 6 with demanding tasks, such as working memory tasks, 7 patients with fibromyalgia do not perform similar to age-8 matched controls and, in fact, perform similar to older 9 controls that are 20 to 30 years older than the 10 fibromyalgia patients and exceptionally carefully matched 11 with respect to education.12 Additionally, in other types of memory 13 performance, like long-term memory or free recall, 14 fibromyalgia patients perform like older adults.15 Now, when one looks by functional imaging at 16 older versus younger adults, you can see that one of the 17 things that older adults do is that in comparison to 18 younger adults that use primarily one hemisphere of their 19 brain, and I'll just point you to the middle slide because20 this is somewhat complicated, certainly on the left side, 21 you can see a little bit more utilization in the older 22 adults. You can see this bilaterality in the older 1 84 2 1 adults, suggesting that they're recruiting more areas of 2 their cortex to actually perform certain cognitive tasks, 3 and you can see very clearly the bilaterality in the older4 adults compared with the younger adults.5 We did a study recently -- this is actually an6 unpublished study -- looking at patients with fibromyalgia7 compared with age- and education-matched controls in a 8 working memory task where the subjects were asked to look 9 at a series of consonants for 1 second. And then in this 10 interval, they were asked to put these in alphabetical 11 order; that is, to perform a complex reorganization task, 12 while the screen was blank, and then they were given a 13 prompt and asked to determine whether or not this S was in14 the proper position with respect to its alphabetical 15 organization. And in this trial, the patients would 16 respond yes because the letter S is in the correct 17 alphabetical position.18 This was subtracted from a condition which we 19 called a maintenance condition where we would demonstrate 20 or show the patients letters that were actually already in21 alphabetical condition and they were just asked to hold 22 those in their memory as a maintenance condition rather 1 85 2 1 than alphabetizing, so that they weren't asked to do a 2 manipulation.3 Then what we did was we looked at the 4 difference between the alphabetizing condition and the 5 maintenance condition in the fibromyalgia patients versus 6 the controls, and you can see a couple of interesting 7 things. I should say that patients with fibromyalgia 8 actually performed equally well on this task. So it 9 wasn't that the task was so hard and that they couldn't do10 it or that they weren't trying. They performed equally 11 well as the control subjects.12 What you can see is that fibromyalgia patients13 showed this bilaterality, bilateral activation in the 14 middle frontal gyrus while alphabetizing, increased 15 activation in the right superior parietal lobe which is an16 area that's specialized for processing of spatial location17 of objects, meaning and storage of items during working 18 memory tasks. They had a midline medial frontal gyrus 19 activation which was associated with eye fields, and they 20 overall showed more activation when alphabetizing than 21 when they were in the maintenance condition. 22 Additionally, there was a region bordering the right 1 86 2 1 inferior frontal gyrus and precentral gyrus in 2 fibromyalgia patients and also the right BA 44 which was 3 homologous to Broca's area in the left hemisphere and an 4 activation of Broca's area 9 thought to be involved in 5 reasoning.6 The control subjects actually did not find 7 this task to be more difficult and the normal controls did8 not show more activation in any part of the brain in the 9 alphabetizing minus maintenance condition. Only a small 10 non-significant region was identified, so that the control11 subjects really did not have to work harder to alphabetize12 compared to the maintenance control, which again 13 identifies the veracity of the patient's complaints, that 14 they're actually feeling that their cognitive abilities 15 have declined compared with what's age-appropriate.16 Now, in thinking about depression and anxiety 17 in fibromyalgia, these psychiatric conditions are neither 18 necessary nor sufficient for the diagnosis of fibromyalgia19 syndrome. As I mentioned a number of times, there's a 20 higher point prevalence than in the general population, 21 and certainly the lifetime prevalence in the tertiary care22 population is quite high, with a study by Epstein and 1 87 2 1 colleagues noting depression at 68 percent and anxiety 2 disorders at 35 percent. And Larry previously showed his 3 data on health care-seeking associated with psychiatric 4 co-morbidity.5 In thinking about how these non-pain symptoms 6 might be linked in a mechanistic way, many of us have 7 focused on the stress response systems, and I'd like to 8 spend a couple of minutes demonstrating some of the 9 mechanisms that may be operative. I certainly don't have 10 time to talk about all the potential mechanisms but I'll 11 just mention a couple.12 The quote that "stress is life and life is 13 stress" is something that I think we all recognize and 14 can't escape, but from a strictly biological sense, 15 stressors are thought of as forces that disturb 16 homeostasis and can include any number of stressors. Now,17 these are counterbalanced by adaptive forces and these 18 adaptive forces are collectively called the stress 19 response systems and they mediate not only central 20 adaptation because under stress, your brain certainly has 21 to adapt, and peripheral adaptation as well because your 22 body has to respond to these forces. 1 88 2 1 The stress response systems, I wouldn't think 2 of them as unitary because different stressors activate 3 different responses, as might be expected, but in general,4 the major players are the hypothalamic-pituitary-adrenal 5 axis and the autonomic nervous system, and these are 6 critical components of the coordinated physiologic 7 response to stress.8 Now, the response to stress because of the 9 central and peripheral factors includes physical but also 10 behavioral and psychological symptoms and these domains 11 have been linked to HPA axis and autonomic system 12 abnormalities.13 So what is a healthy HPA axis? I'll focus on 14 the HPA axis, because that's what I do, and show you some 15 data on the HPA axis, but I don't want to suggest that 16 this is the only potential mechanism that could be 17 involved in fibromyalgia syndrome and certainly autonomic 18 nervous system pathways have been implicated as well.19 So what's healthy? Healthy is that there's a 20 wide dynamic range and what that means is that there's a 21 circadian variation with a high cortisol in the morning 22 and low cortisol in the evening, a very wide dynamic 1 89 2 1 range. It should be responsive to physiologic and 2 stressful stimuli. We don't like to see putzy responses 3 to stress. We like to see people whose cortisol levels go4 up in response to stress and that's healthy. It's also 5 sensitive to feedback suppression and one measures that by6 using dexamethasone, but you can also measure it in the 7 laboratory and we like the HPA axis to be able to shut off8 after it's been activated. And so what's really a healthy9 stress response is that it ought to be responsive and it 10 ought to be resilient.11 So what happens in patients with fibromyalgia 12 syndrome? I'll just show you a study that we've recently 13 completed and again is unpublished looking at a number of 14 different ways to stress the HPA axis, first using a low-15 dose physiologic injection of corticotropin-releasing 16 hormone and then coming back with graded doses of 17 dexamethasone. I think we could have taken people and 18 done public speaking three days in a row or all kinds of 19 other things, but we used this as a potential marker for 20 elevated cortisol and what happens in response to this 21 facsimile of a stressed HPA axis.22 First, I'll show you that the resiliency of 1 90 2 1 the HPA axis in fibromyalgia patients isn't quite normal. 2 It doesn't tend to quite get back to what happens in a 3 normal individual.4 More interesting is what happens if you keep 5 doing this, if you have these repeated stressors, and what6 I'd like you to focus on is this green line first which is7 a healthy control population. This is the morning after. 8 These are salivary cortisol measurements the morning after9 the CRH stimulation test. They have a fairly normal high 10 cortisol, not quite as high as we'd like it to be, so it's11 still a little bit suppressed, but you can see a very nice12 drop in the cortisol in the evening and then on a baseline13 day when we don't do anything to them, they have this very14 nice wide dynamic range. If you give them dexamethasone, 15 they're suppressed in the morning but again give you this 16 very low cortisol in the afternoon, and then when you 17 don't do anything to them, they go back up with this very 18 nice wide dynamic range. Again even with .5 micrograms of19 dexamethasone, they suppress in the morning but again they20 still have this low evening level.21 And I'd ask you to contrast that with the 22 patients with fibromyalgia. They certainly do suppress in 1 91 2 1 response to the oCRH, but in contradistinction to the 2 patients that are normal, they actually fail to go back to3 a normal low evening cortisol. And as we get going with 4 the paradigm, you can see that they do give you a little 5 bit of a wide dynamic range on the second day. You hit 6 them with dexamethasone, they suppress, but then they 7 actually reverse their circadian rhythm. And then you 8 start to see an impact on the dynamic range of the HPA 9 axis over time, so that the difference between morning and10 evening becomes obliterated. And when you hit patients 11 with a half a milligram of dexamethasone, you start to see12 this rebound or reversal of circadian rhythm.13 What this demonstrates is that with repeated 14 facsimiles of stressors, that patients with fibromyalgia 15 syndrome actually don't have the responsiveness and 16 resiliency that one might see in a normal individual and 17 graphically, you can see that on these non-stressed days, 18 that means that the difference between the morning and the19 evening cortisol becomes blunted and that one can actually20 see even a reversal of that circadian variation in 21 patients with fibromyalgia syndrome.22 Now, I don't have time to talk about similar 1 92 2 1 studies with the autonomic nervous system, but I think 2 that it's been shown by a number of studies that their 3 altered sympathetic and sympathoadrenal dynamic 4 variability, including a reduced heart rate variability --5 so again, there's this lack of this dynamic range that one6 would expect in a normal individual -- altered stimulus-7 induced blood flow and altered stimulus-induced release of8 noradrenaline and even adrenaline in some studies.9 So that, there is evidence in fibromyalgia 10 syndrome patients, not only by groups in this country but 11 groups all over the world, that there's an altered dynamic12 function of the stress response systems. The problem is, 13 is that, it's not always the same in every patient, and I 14 think that you ought to now keep in mind, with respect to 15 biological subsets, that these endocrine systems are much 16 like other endocrine systems that we're more familiar 17 with; that is, for example, thyroid disease. If you have 18 hypothyroidism, you can present with fatigue, but if you 19 have hyperthyroidism, you can present with fatigue and 20 musculoskeletal aches, and in hypothyroidism, you can also21 present with musculoskeletal aches.22 So I think what we need to keep in mind is, as 1 93 2 1 with this neuroendocrine system as well as other 2 neuroendocrine systems, that there's a concept of an 3 allostat and what that means is that there's an optimal 4 operating range and that you can go too low or you can go 5 too high and it's no longer optimal, and that some of the 6 symptoms of patients with alterations in these stress 7 response systems may actually overlap. And some of the 8 times, for example, a potential dichotomy between chronic 9 fatigue syndrome and fibromyalgia, even though the same 10 system may be involved, the symptom complex may be a 11 little bit different.12 There's also the concept that the function of 13 these stress response axes because of their nature can 14 differ under different physical and psychosocial stress. 15 So that, whenever you have an allostat or some kind of a 16 guide that ought to stay centered, the stress on that 17 system changes, depending on the load that's applied to 18 it, and there can be minor load and there can be heavy 19 load, and the function of the allostat may perform as well20 or not quite as well, depending on the load that's applied21 to it.22 I'd also like to note that there's a very 1 94 2 1 strong drive to maintain the overall hormone levels. So 2 if anybody thinks you can measure a 24-hour urine cortisol3 and get significant findings, you can't because there's a 4 very strong drive, as you saw in my studies that I 5 presented. If you go really low in the morning, you go 6 higher in the afternoon, so that there's a very strong 7 drive to maintain those levels.8 And I should note that current therapies 9 influence the expression of key components of the system. 10 Tricyclic antidepressants and SSRIs, for example, 11 influence the expression of mineralocorticoid and 12 glucocorticoid receptors in the central nervous system 13 perhaps better than any other treatments that are 14 available, and I should also note that exercise which is 15 an effective therapy in this condition is known to 16 modulate the set point of the allostat.17 So what are the implications of all of these 18 comments for drug therapy? Well, I would say that 19 fibromyalgia syndrome, whether it's clinically diagnosed 20 or laboratorially diagnosed, is certainly recognizable. 21 As I said before, this does not exclude the likelihood of 22 subsets of patients with different underlying mechanisms, 1 95 2 1 but when a patient with fibromyalgia syndrome walks into 2 the office in my clinic, I can make the diagnosis 3 reliably, and I think most clinicians can do so or most 4 thoughtful clinicians can do so.5 Clinically important improvements in pain are 6 likely to occur in response to treatments that address 7 central mechanisms and reduced pain is likely to improve 8 the health-related quality of life in patients with 9 fibromyalgia. Non-pain symptoms are also important to the10 health-related quality of life in these patients and 11 influence health care-seeking and utilization.12 I should point out that these non-pain 13 symptoms often cluster with central pain and 14 neurobiological mechanisms actually may be shared as a 15 cause for pain and non-pain symptoms or at least they may 16 co-occur. And clinically-significant improvements in non-17 pain symptoms are also likely to result in global 18 improvement in patients with fibromyalgia.19 I'll conclude there and thank you for your 20 attention. I'm happy to take any questions.21 (Applause.)22 DR. FIRESTEIN: Thank you very much. 1 96 2 1 Are there any questions?2 DR. GIBOFSKY: Leslie, I was intrigued by your3 slide earlier showing the mechanisms involved in spinal 4 central sensitization or I think you referred to it as 5 activity-dependent plasticity. I'm wondering, would it 6 follow from that that a sine qua non for any pharmacologic7 agent to treat fibromyalgia or any of the manifestations 8 of fibromyalgia would have to be some effect on the 9 central nervous system, therefore by extension 10 physiologically an agent being able to cross the blood-11 brain barrier.12 DR. CROFFORD: That's a good question. 13 Certainly many of the agents that we know impact central 14 sensitization, impact some of the modulatory inputs. So 15 we talked about NMDA, for example, and the NK1 receptor 16 antagonist, for example, that might potentially influence 17 things like the effects of excitatory amino acids or 18 substance P, for example. I would think that those kind 19 of mechanisms or those kinds of agents might have to cross20 the blood-brain barrier, but I'd certainly want to see 21 data in that regard.22 With respect to the other types of agents that 1 97 2 1 we know influence what goes on at the spinal cord, agents 2 that influence the availability of norepinephrine and 3 serotonin certainly do exist and are among those that are 4 the most effective for this condition, which obviously you5 can't totally draw conclusions from that, but certainly it6 suggests the possibility that influencing those central 7 factors may be important.8 Other types of agents, like non-steroidals, 9 for example, and I think it's been mentioned a number of 10 times that they don't seem to be quite as effective. 11 However, as you know and I know, there's certainly central12 prostaglandin expression and I don't think it's out of the13 realm of possibility that certain agents that might affect14 peripheral mechanisms may have a positive impact, but I 15 doubt that they will be as effective as agents that 16 address some of these particular central mechanisms.17 DR. FIRESTEIN: Dr. Abramson?18 DR. ABRAMSON: Leslie, the tender points are 19 obviously important for the diagnosis. Is there any data 20 that's been able to validate tender points with regard to 21 fMRI or other kinds of pain thresholds that distinguishes 22 these areas from other areas? 1 98 2 1 DR. CROFFORD: My response to that is that 2 there's nothing special about the tender points. I think 3 you saw in Larry's slide that patients with fibromyalgia 4 are tender to control point palpation as well and that the5 selection of the tender points -- I was not present. I 6 think Larry probably was present in the formulation of 7 these tender points. The thing about them is, is that, 8 they're widespread, so that you have to exhibit 9 hyperalgesia, allodynia in a lot of different body areas 10 to cross the threshold of 11 of 18. A lot of people have 11 strong feelings about whether the tender points are useful12 or not.13 So I think from a historical standpoint, you 14 could probably pick fewer tender points that are above and15 below the waist and get a similar feeling that this was a 16 patient that exhibited widespread rather than regional 17 allodynia and hyperalgesia, and there's really nothing 18 special about them.19 Most of the imaging studies have been done 20 using alternate mechanisms, but obviously it's difficult 21 with an fMRI to get in there and exert pressure. I think 22 Larry has done that with SPECT using tender points, but 1 99 2 1 you get the same thing no matter what you do. Dan Clauw 2 has done it with pressure on the thumbnail. The Gracely 3 studies were done with a thumbnail smasher, and I've done 4 similar studies with Ken Casey using a thermal probe that 5 give you similar results.6 So the answer is they're a very useful tool 7 for identifying patients in the clinic. They're simple. 8 They're reliable. They're validated. There's nothing 9 special about them.10 DR. FIRESTEIN: One last question.11 DR. STAUD: Leslie, you showed us a lot of 12 data about the abnormalities in the HPA axis in 13 fibromyalgia patients compared to normal controls. Now, 14 this is group data, and I was wondering if you could tell 15 us something about the relationship to individuals, 16 particularly in terms of predicting abnormalities of the 17 HPA axis.18 DR. CROFFORD: We've looked at that a lot, 19 Roland, and tried to figure out how we could use clinical 20 data to predict who was going to have the HPA axis 21 abnormalities and we've just failed. We've certainly 22 tried to do cluster analyses and I'm going to ask Dan to 1 100 2 1 help me with some of these data that we have, some older 2 data, to try to look at a clinical symptom profile that 3 would help us to predict which patients are going to 4 exhibit the most severe responses, but we haven't been 5 able to do that.6 What you point out is correct, and I'd like to7 certainly make that clear to the audience, that there's a 8 spectrum of responsiveness, just like there's a spectrum 9 of every other biological measure that we vary, and when 10 you look at group means, there are going to be some that 11 are going to look more normal and some that are going to 12 look more abnormal, and I certainly would agree with that.13 You may be able to use some paradigms that 14 we're working on to actually subset the patients. As 15 Dennis pointed out, there probably are biological subsets 16 and we're continuing to try to develop simple measurement 17 techniques, so that we can actually do subsetting.18 DR. FIRESTEIN: Thank you very much, Leslie.19 The last talk of this session will be Dr. 20 Clauw talking about Post-ACR Diagnostic Criteria, and then21 we'll take a short break.22 DR. CLAUW: Let me also begin by 1 101 2 1 thanking/acknowledging the people on the FDA. Jim Witter 2 first asked me to come and talk to the agency over three 3 years ago about fibromyalgia because the agency was 4 interested in fibromyalgia and viewed that this is where 5 it should be. More recently, Lee has been a very strong 6 advocate of the whole fibromyalgia construct. This is a 7 secret that most people won't know till August or so, but 8 he and I actually co-edited an issue of Bailliere's, an 9 entire issue, having to do with fibromyalgia. So look at 10 how far Lee has come.11 (Laughter.) 12 DR. CLAUW: I'm certainly not going to be 13 presumptuous enough to tell this audience how we should in14 the future define chronic pain conditions, but for 15 purposes of my talk, I just want to make a couple 16 distinctions. These are distinctions that have already 17 been made by both Larry and Leslie about what is different18 about fibromyalgia than some of the diseases that we as 19 rheumatologists or members of the panel might be more used20 to seeing. But I think that it's really important to 21 distinguish between peripheral or nociceptive pain 22 syndromes which are primarily due to inflammation or 1 102 2 1 damage in peripheral tissues which are classically quite 2 responsive to both NSAIDs and opioids and where behavioral3 factors are relatively minor contributors to symptom 4 expression and central or non-nociceptive pain syndromes 5 of which fibromyalgia would perhaps be the poster child.6 Again, you've heard a lot about this, but I 7 think that as rheumatologists, the only non-nociceptive 8 pain syndrome that we see is fibromyalgia which is perhaps9 why we find it so different and so hard to reconcile some 10 of what we think vis-a-vis pain and what should make it 11 better and how these people should act with all the other 12 diseases that we, in fact, take care of and we take care 13 of quite well.14 But fibromyalgia is not the only central pain 15 syndrome. Irritable bowel syndrome, vulvodynia, 16 interstitial cystitis, tension and migraine headaches. 17 There's a whole host of illnesses where the pain is not 18 coming or occurring because of some damage or inflammation19 in peripheral tissues; it's instead occurring because of 20 some central nervous system process or some process that's21 leading to disturbances in pain processing.22 Of course, with any attempt to make a clean 1 103 2 1 demarcation, there are going to be illnesses or diseases 2 that don't fit nicely into one category or another. An 3 example of this would perhaps be neuropathic pain. 4 Another example would be low back pain where certainly 5 subsets of individuals with low back pain have peripheral 6 causes for their pain and subsets have more central causes7 for their pain.8 But, again, the main reason to point this out 9 is that what I'm going to do when I talk about some of the10 different outcomes that have been studied in fibromyalgia 11 is in particular point out the outcomes that are different12 in fibromyalgia, especially with respect to how they 13 relate to other symptoms than they are in peripheral pain 14 syndromes.15 One of the advantages I have in giving this 16 talk is there have been a couple nice meta-analyses that 17 have been done looking at effect sizes of various types of18 treatments for fibromyalgia. I'll show a couple slides 19 from this study that was done by Rossy and published in 20 Annals of Behavioral Medicine in 1999 that looked at 21 pharmacologic therapy, exercise, and cognitive behavioral 22 therapy and looked at the different domains that 1 104 2 1 theoretically could be improved: symptoms, psychological 2 status and, in italics here, functional status.3 What you see here is that for pharmacologic 4 therapies, there are moderate effect sizes for 5 improvements in symptoms and improvements in psychological6 status, but really poor effect sizes with respect to 7 pharmacologic therapies being able to change functional 8 status in fibromyalgia.9 Exercise does about the same with respect to 10 symptoms and psychological status, and even though 11 exercise theoretically is something where we're teaching 12 people how to improve physical function, you reproducibly 13 see again modest effect sizes in functional status when 14 exercise is used as a treatment for fibromyalgia.15 Then finally, cognitive-behavioral therapy. 16 Again, moderate effect sizes here for symptoms and 17 psychological status and sort of a low effect size with 18 respect to functional status.19 If you look at specific classes of 20 medications, you see here that, by and large, the 21 antidepressants are the most effective class and that they22 again have moderate effect sizes with respect to symptoms 1 105 2 1 and lesser effects with respect to both psychological 2 status and functional status.3 Muscle relaxants. This is a little bit of an 4 aberration because Flexeril, which is really a tricyclic 5 drug, is included in muscle relaxants. So the 6 overwhelming majority of these compounds that are studied 7 under the category of muscle relaxants are in fact 8 cyclobenzaprine which is a tricyclic compound. This is 9 probably why you see that they perform very similarly to 10 what is largely tricyclic compounds in the antidepressant 11 category.12 And then finally nonsteroidal anti-13 inflammatory drugs. Don't be misled by this n of 1 study 14 where one single study did, in fact, lead to a moderate 15 effect size in psychological status. None of us really 16 think NSAIDs make psychological status better and again 17 here you see that NSAIDs don't lead to any improvement, in18 fact, in this single study led to a worsening, in 19 functional status.20 Leslie Arnold did a nice meta-analysis looking21 only at tricyclic compounds in fibromyalgia and again 22 looking at pooled effect sizes and found that the domain 1 106 2 1 that tricyclics affected most predictably was sleep. 2 Physician global, pain, fatigue and patient global all 3 were affected in the sort of range that we classically 4 think of as moderate effect sizes.5 Here, you see that tenderness was the most 6 difficult domain to improve and this is something that we 7 see over and over again, that tenderness, especially as 8 measured by tender points, is not something that generally9 gets better in clinical trials of fibromyalgia. There are10 exceptions to this, but it's not something that is as 11 responsive to therapy as we might hope or think that it 12 should be.13 So what I'm going to do is go through and talk14 about potential outcome measures in fibromyalgia. I'm 15 going to spend the most time focusing on pain and on 16 functional status because those are the domains I think 17 that are perhaps most controversial vis-a-vis the 18 discussion that's going to transpire after the talks 19 today. So I'm going to present a fair amount of data with20 respect to whether these domains move or not in the 21 setting of fibromyalgia.22 When we're talking about pain, there's a whole 1 107 2 1 bunch of different issues. Again, all of you are quite 2 familiar with pain and how it's classically been studied. 3 One of the things that I think has been interesting about 4 this recent movement in those of us who study fibromyalgia5 in doing clinical trials in this spectrum is that if I was6 studying RA or OA, I really wouldn't have much of a choice7 as to what outcome measure that I chose. If I was 8 studying osteoarthritis, I would be using the WOMAC. If I9 was studying rheumatoid arthritis, I would be using one of10 the ACR 20, 50, or 70, but when you study fibromyalgia, 11 basically you have a blank slate. You can do anything 12 that you want to do and then try to justify why it is that13 you did that.14 So I'll talk about some of the things that I 15 think in fact have been fairly innovative in some of the 16 clinical trials that have been done in fibromyalgia just 17 because of the fact that we, if you will, are allowed to 18 innovate because there's basically no one saying that this19 is how we should or need to study fibromyalgia.20 The next couple slides are slides that I stole21 from Dave Williams in our group, from a talk that he gave 22 about a year or so ago, talking specifically about pain. 1 108 2 1 But I'm just going to show a couple slides showing how 2 different artists have tried to depict the complex symptom3 that it is that we call pain. Now, I wish I knew the 4 actual artists here, but since I was putting this together5 on the fly, I didn't actually have a chance to talk to 6 Dave about who the artists are but perhaps some of you 7 know.8 This is a picture that most of us in 9 rheumatology have seen at one time or another looking at 10 the pain associated with gout and showing how sort of the 11 gnawing, grabbing, aching pain that's associated with gout.12 Then finally, this is another depiction by an 13 artist of the pain that she was describing in herself. 14 She, in retrospect, is thought to actually have 15 fibromyalgia.16 And then contrast this with our visual analog 17 scale. Basically, we ask people in clinical trials to put18 an X on the line and say that they have pain somewhere 19 between no pain and as bad as it could possibly be.20 Now, some of the problems with visual analog 21 scales and with current measures of pain measurement. 22 With respect to the VAS in particular, it isn't a very 1 109 2 1 good measure with respect to the dynamics of measurement 2 in that when someone moves from 3 centimeters to 1 3 centimeter on a visual analog scale, that isn't the same 4 as someone moving from 10 centimeters to 8 centimeters. 5 So there's a number of issues with respect to the 6 different areas of a visual analog scale are used 7 differently by different people. So there are scaling 8 problems with visual analog scales.9 Another problem with the VAS is that it only 10 captures a single dimension of the pain experience, and 11 multidimensional measures, like the McGill, are certainly 12 richer with respect to looking qualitatively at the 13 differences both in different types of pain as well as the14 differences in how different types of treatments might 15 lead to a differential qualitative response with respect 16 to pain.17 I'm not going to talk a great deal about these18 two issues. I am going to allude, though, to this issue 19 of the problems with retrospective report of a symptom 20 because some of the data that happens to have been 21 collected in the setting of fibromyalgia with respect to 22 pain measurement is, in fact, relevant to anyone that's 1 110 2 1 studying pain vis-a-vis problems with paper and pencil 2 diaries and perhaps improvements that could be made by 3 looking at electronic assessments of diaries.4 And then finally some of the other problems 5 with the current measurements of pain is that they miss 6 other important domains that might be at least as 7 important as the actual intensity of the pain.8 This is a scale that although it certainly has9 not been well enough validated to be used in a trial for 10 registration of a drug, it's an instrument that Rick 11 Gracely took about 15 or 20 years to develop that has 12 verbal anchors where basically individuals, both patient 13 groups and control groups, were given these verbs in a 14 mixed-up version and told to rate these verbs with respect15 to the intensity. And this, with all the work that's been16 done on it, now turns out to be actually a fairly linear 17 scale in contrast to a VAS and such that a movement in 4 18 points from 20 to 16 is the same as a movement in 4 points19 from 4 to 0. Again, this is of interest, I think, and 20 something that we all perhaps could aspire to and begin 21 using in pain trials but isn't nearly well enough 22 validated to be used in trials that the FDA may be looking 1 111 2 1 at.2 Another issue that was particularly brought 3 home by an article published by Arthur Stone and his group4 last year in the British Medical Journal was the poor 5 compliance that typically occurs with paper and pencil 6 diaries. I think most of you are probably aware of this 7 study, but for those of you who aren't, you should be. 8 This is a study where Stone and his colleagues took a 9 group of chronic pain patients over 21 days. Unbeknownst 10 to these individuals, there was a microchip embedded in 11 their paper diaries, such that the investigators could 12 tell when these diaries were opened and closed. They 13 asked people to recount their pain in a classic sort of 14 paper and pencil diary way that we all are familiar with, 15 and when they looked backwards at compliance rates, even 16 though individuals said that they were compliant, 89 17 percent of their entries, even when you gave people a 30-18 minute window vis-a-vis compliance, the actual compliance 19 rate was only 11 percent. That is, only 11 percent of the20 entries could have occurred within 30 minutes of when the 21 patients said they occurred because the only time they 22 could occur is if someone had their diary open. 1 112 2 1 The scary thing about this study was -- all of2 us who do randomized clinical trials know about backward 3 filling. We all see people that come into our office and 4 are sitting in the exam room and filling in the last week 5 of their diary while they're in the exam room, and 6 although that has some problems, at least they 7 theoretically are recalling their pain and trying to 8 retrospectively sort of integrate their pain and that's 9 what they're recording.10 One of the things, though, about this study 11 was that a surprising number of people forward filled 12 their diaries. A surprising number of people filled their13 diaries in, they closed the diary Tuesday, it wasn't 14 opened until the investigators opened it on Friday, and 15 yet they had recordings in for Wednesday, Thursday, and 16 Friday. So the forward filling, as well as a number of 17 other issues, really raise serious questions with respect 18 to the validity of paper and pencil diaries and to the 19 validity of the data that are captured with paper and 20 pencil diaries.21 Because of this, our group has been interested22 in looking at what Stone and his colleagues have termed 1 113 2 1 ecological momentary assessments. Again, there's a number2 of people that have been doing work in this field for an 3 awful long time. This is just sort of the last iteration 4 of this work. This is one such device. There are a 5 number of different devices on the market and a number of 6 different companies in fact that are marketing devices 7 looking at the real-time collection of systems. This 8 happens to be a palm-based device that randomly prompts 9 individuals as many times a day as you figure that you can10 bother people to enter whatever symptom it is that you 11 want them to enter. In this case, we were looking at pain12 randomly prompted five times a day over the course of 13 first a non-interventional trial and then more recently an14 interventional study.15 This was alluded to earlier vis-a-vis some 16 work that Alex Zautra did showing that the levels of 17 stress in fibromyalgia subjects lead to differences in 18 their pain report. Every-day stress leads to differences 19 in their pain report. This might be what we're seeing 20 here. You can't see these yellow lines very well, and I 21 apologize for that, but you see the tremendous variability22 in this one day, for example, someone who went from a 0 to 1 114 2 1 a 9 over the course of a single day with respect to a VAS 2 rating of their pain score. This variability in fact was 3 very common in the fibromyalgia subjects, this tremendous 4 variability from hour to hour that occurred when we 5 prompted people five times a day to record their pain.6 One of the other things that was interesting 7 and now this -- these are data from Cypress' phase II 8 study of milnacipran. I'm not going to present the 9 results of the data. All I'm going to present are the 10 data looking at the differences between different measures11 of pain, whether you're looking at a diary that's filled 12 out or a visual analog scale that's filled out in a clinic13 versus an electronic diary versus a paper and pencil diary.14 There were a couple things that we saw both in15 this study as well as in a smaller non-interventional 16 study that we had done at Georgetown using the same palm-17 based recordings of pain, and that is, that the random 18 prompt recordings of pain were much lower than the 19 clinical reportings of pain that occurred at the exact 20 same time. So you see here that as you move from random 21 prompt where we averaged 50 random prompts to get this 22 average of 11.9 to daily ratings of pain where there were 1 115 2 1 14 that were given over a 2-week period to weekly ratings 2 to weekly paper ratings, you see here a large difference 3 in the baseline ratings of pain of individuals when that 4 pain is recorded in an EMA type of momentary way versus in5 a clinical sample here, again the way that we typically 6 record pain.7 Now, if that was consistent throughout the 8 clinical trial, that wouldn't cause any problems. So if 9 there was always this 4-point difference between the 10 random prompts and the weekly paper recordings of pain, 11 then that theoretically wouldn't cause a problem. All the12 measures would just be elevated in the weekly paper 13 ratings.14 But that isn't in fact what was found in the 15 Cypress study. What was found is that the difference at 16 the baseline was the 4-unit difference that I showed you, 17 whereas the difference at the end of the trial was 2 18 units. So what happened is there seems to be something 19 different about psychologically or perhaps there's demand 20 characteristics on the subjects when they're entering a 21 clinical trial, but there's a larger offset here between 22 the random prompts and the clinic visit here rating of 1 116 2 1 pain of 4 units -- now, this is on a 0 to 20 scale, not a 2 0 to 10 scale, just so you all are oriented -- than there 3 is at the end of the study where this difference between 4 the random prompts and the clinic samples average was 2 5 units.6 Now, that 2-unit difference between the 7 beginning and the end of the trial would normally be 8 considered to be something that we would wrap under the 9 umbrella of a placebo response, but it's not a placebo 10 response. It's a measurement artifact. It's an artifact 11 of the fact that we classically have measured pain using 12 these paper and pencil instruments that at least 13 theoretically have a lot of inherent biases with respect 14 to recall, with respect to demand characteristics, with 15 respect to other things that influence how people report 16 pain. And this is just showing you here how this 17 difference occurred over the course of the trial.18 So to summarize here, the random prompt pain 19 is extremely variable in fibromyalgia. We haven't yet 20 done studies to show that it's more variable in 21 fibromyalgia or other central pain syndromes than it is in22 a peripheral nociceptive pain syndrome, but I think that 1 117 2 1 that would be the most logical hypothesis, that if someone2 has nociceptive pain that is occurring because of 3 activation of a nociceptor, that that pain might be more 4 constant and more consistent from hour to hour and day to 5 day and week to week than central pain because there's so 6 many things that influence central pain, i.e., day-to-day 7 stress or hour-to-hour stress that people are experiencing.8 Interestingly enough -- and again, I'm not 9 going to present all this data -- despite this difference 10 that I've shown you which is quite interesting and 11 intriguing, it didn't really make a huge difference in the12 Cypress trial. All of the measures in fact tended to be 13 equally responsive to change, although there are issues, I14 think, with the validity of paper and pencil diaries vis-15 a-vis the Stone work and some of the other work that's 16 been published. It didn't seem to make a big difference 17 with respect to responsiveness to change whether we were 18 collecting these outcomes electronically in random prompts19 or whether we were collecting them with paper and pencil 20 and looking at people's recall of information.21 Now, with respect to functional status, I'm 22 going to make a distinction between what people are 1 118 2 1 reporting vis-a-vis functional status in fibromyalgia and 2 what really is going on vis-a-vis functional status in 3 fibromyalgia because what I hope to convince you of is, 4 again, this is an area that is inherently different in 5 fibromyalgia than it is in nociceptive pain syndromes, 6 where there is more than just a decrease in activity and 7 the sort of classic dysfunction that we think of, for 8 example, in OA of the knee, going on in the average person9 that has fibromyalgia.10 So the first thing I'll talk about is 11 something that was alluded to by both Leslie and Larry, 12 and this is something that Larry is largely responsible 13 for. He was giving Doug Drossman a lot of credit for 14 doing this in IBS, but his group was the one and it still 15 is the one that's really been the leader in doing this in 16 fibromyalgia, showing that people who we recruit in 17 tertiary care samples are different than people who are in18 primary care samples who are different than people who are19 in the general population. And that is, the tertiary care20 samples have higher levels of distress, higher levels of 21 cognitive factors, higher levels of psychiatric co-22 morbidities, and higher levels of other sort of 1 119 2 1 psychological factors.2 Now, the problem with all the stuff on the 3 right side of the screen here is that this leads to 4 dysfunction and this, in particular, leads to self-report 5 of dysfunction. Yet these things are not very amenable to6 pharmacologic therapies. These are the things that 7 cognitive-behavioral therapy really tries to target and 8 tries to impact on because when someone gets to the point 9 that they have one or more of these psychological, 10 behavioral, cognitive factors that are driving symptom 11 expression, that are driving self-report of symptoms, just12 giving them a drug isn't necessarily going to make that 13 better.14 And so another way of depicting this -- this 15 is another slide that I borrowed from Leslie in this case 16 of this poor little mouse here in an inner tube -- is that17 some combination of stress plus bad genes plus environment18 leads to symptom expression in fibromyalgia.19 Those of us who were trained as internists and20 rheumatologists have a tendency to focus on symptoms and 21 there's nothing wrong in particular with focusing on 22 symptoms, but over the last 8 or 10 years, as I've worked 1 120 2 1 closely with psychologists and psychiatrists, 2 psychologists and psychiatrists in fact focus on different3 things than we focus on. They focus on psychological and 4 behavioral consequences of symptoms, things like decreased5 activity, like poor sleep, like increased distress and 6 maladaptive illness behaviors, and the reason they focus 7 on that is they know these all make symptoms worse.8 The reason I show this slide is again to look 9 at the interaction between symptoms and function in 10 fibromyalgia and realize that there isn't a direct 11 relationship here between symptoms and decreased function.12 I draw the arrows, but there's not a direct relationship. 13 You could imagine a scenario where someone with 14 fibromyalgia who's had it for 10 years, is on disability 15 for fibromyalgia, if and when we ever develop the magical 16 drug that makes symptoms better in fibromyalgia, they 17 could take that drug and nothing would change vis-a-vis 18 these types of factors because fibromyalgia has 19 essentially become a way of a life. What's happened to 20 this person with fibromyalgia is their pain, their 21 fatigue, has led to isolation, has led to limitations in 22 their day-to-day activity, and just because they take a 1 121 2 1 drug that makes them feel better doesn't mean that they're2 dramatically then going to have an improvement in 3 functional status.4 Now, if you look at functional status in 5 fibromyalgia, there's a couple outcome measures that you 6 can theoretically use and that would be primarily the 7 Fibromyalgia Impact Questionnaire. The Fibromyalgia 8 Impact Questionnaire has a unique distinction of being the9 best outcome measure of functional status in fibromyalgia 10 and the worst outcome measure of fibromyalgia functional 11 status because it's the only disease-specific outcome 12 measure in fibromyalgia.13 Some of the reasons that many of us are not 14 enamored with the Fibromyalgia Impact Questionnaire are 15 that some of the questions that it asks are fairly gender-16 specific, and I might get in trouble by saying that 17 because many women don't even do these things any more 18 like wash dishes by hand. So these are perhaps things 19 that might have been relevant 20 years ago when this 20 outcome measure was developed, but they're perhaps not 21 very germane right now. In fact everyone that's used the 22 FIQ has noted the problem with missing items in the FIQ. 1 122 2 1 People just won't fill out some of these items, like wash 2 dishes by hand, prepare meals, or vacuum a rug, because 3 they don't happen to apply to that particular individual.4 Another problem with the FIQ is it was meant 5 as a multidimensional measure, not a pure functional 6 status measure. So when it measures function, it in fact 7 looks at domains like anxiety and depression as symptoms 8 of dysfunction. So it's a measure that is somewhat 9 contaminated. It's not a pure functional status measure. 10 It's a measure that's contaminated by, if you will, 11 psychological factors, like anxiety and depression, which 12 arguably should be measured independently by a scale that 13 purely is measuring depression and anxiety rather than by 14 an aggregate scale that includes in fact all of those 15 different measures.16 Having said that, the FIQ is fairly responsive17 to change in many studies that have been done in 18 fibromyalgia, but one particular problem with the FIQ is 19 this floor effect. These are data from the Cypress study 20 just to illustrate real data rather than just tell you 21 something, and this is at the end of the Cypress study. 22 The number of individuals here in the bar graphs, the 1 123 2 1 frequency of scores on the FIQ, and you see that at the 2 end of this study, there were 16 individuals who had 0's 3 on the Fibromyalgia Impact Questionnaire and a substantial4 number of individuals who had very low scores on the 5 Fibromyalgia Impact Questionnaire.6 Again, the problem with the Fibromyalgia 7 Impact Questionnaire is that it was developed by Rob 8 Bennett for use in tertiary care of fibromyalgia which is 9 what he was seeing. It doesn't actually perform nearly as10 well when you start to do a randomized clinical trial and 11 you aim for looking at primary care patients with 12 fibromyalgia because a number of individuals will have 13 either pre-treatment measures or, in particular, post-14 treatment measures that are at the end of this continuum. 15 They're basically unmeasurable because of the floor effect.16 This shows the physical component summary 17 score of the SF-36. I indicate here just so you don't get18 confused that the higher number is higher function in the 19 SF-36, whereas lower number is higher function in the FIQ.20 You see here that there isn't really a floor effect with 21 the SF-36. The problem, though, with the SF-36 and the 22 PCS score is that it's a generic health status measure and 1 124 2 1 thus it's not nearly as responsive to change as the FIQ is.2 The other measures of functional status that 3 could theoretically be used in a study of fibromyalgia 4 would include the Health Assessment Questionnaire or the 5 Modified Health Assessment Questionnaire or an instrument 6 that Fred Wolfe published about three or four years ago 7 which are some of the items of the MHAQ which he called 8 the Fibromyalgia HAQ. The problem is that no one has ever9 used either of these in a randomized, controlled trial of 10 fibromyalgia. So there's absolutely no data on the MHAQ 11 or this new measure that Fred developed with respect to 12 using it in a randomized clinical trial.13 I want to just talk briefly. You probably 14 wouldn't imagine that I would come and talk to an FDA 15 panel on drugs, about cognitive-behavioral therapy and 16 exercise, but I'm just going to briefly present the 17 results of this study that were published in JAMA a couple18 months ago because I think it's very illustrative with 19 respect to this dichotomy between function and symptoms 20 and this spectrum of illness.21 This study happened to have been done in 22 returning Gulf War veterans, and for those of you who 1 125 2 1 don't know the whole story of Gulf War Illness, Larry 2 alluded earlier to the fact that multiple different names 3 have been used to describe the spectrum of illness that we4 now call fibromyalgia. Things like shell shock and 5 DeCosta syndrome, in fact, were terms that were used after6 World War I and World War II to describe the returning 7 veterans from those conflicts who had chronic pain and 8 chronic fatigue and other symptoms that we might in the 9 year 2003 call fibromyalgia or chronic fatigue syndrome.10 As we should have perhaps expected after the 11 first Gulf War, a number of veterans returned with 12 otherwise unexplained pain, fatigue, memory problems, and 13 this constellation of symptoms that Leslie and Larry both 14 talked about.15 A number of different studies have been done 16 looking at this constellation of symptoms and syndromes, 17 and they've all concluded the same thing, that there's no 18 unique cluster of illness or syndrome that occurred in 19 returning Gulf War veterans, that the cluster of symptoms 20 that occurs in returning Gulf War veterans can also be 21 found in the general population and the general population22 goes by names such as fibromyalgia, chronic fatigue 1 126 2 1 syndrome, or somatoform disorders.2 The other thing that these studies have found 3 is that in fact after every war the U.S. has ever been 4 involved in, there have been a subset of veterans who have5 returned with these symptoms and these complaints.6 Then finally, with the exception of a single 7 study suggesting that perhaps vaccines given right at the 8 time of deployment might lead to a higher rate of this 9 spectrum of illness in deployed Gulf War veterans. All of10 the other studies that have been done, now about $240 11 million worth of work that's been done in the United 12 States, have all suggested that no single environmental 13 exposure that occurred in the theater of operations in the14 first Gulf War could have been responsible for the 15 symptoms that the returning Gulf War veterans returned 16 with.17 So the CDC late in the 1990s did this series 18 of population-based studies, a couple of which Leslie 19 alluded to, and coined the term chronic multi-symptom 20 illness to describe this constellation of pain, fatigue, 21 memory problems, that sometimes also includes mood 22 disturbances, but in fact affects about 10 to 15 percent 1 127 2 1 of the population in the U.S. and in fact in most other 2 developed countries that it's been looked at.3 This is what makes up this umbrella of chronic4 multi-symptom illnesses. This includes diagnoses like 5 fibromyalgia, multiple chemical sensitivity, chronic 6 fatigue syndrome, somatoform disorders, and what I've 7 euphemistically referred to here as exposure syndromes. 8 The only way you can get Gulf War Illness is to have been 9 deployed to the Gulf War. You can't get Gulf War Illness 10 if you didn't go to the Gulf War, yet the symptoms that 11 people experienced that came back from the Gulf War are 12 exactly the same as the symptoms of those who have 13 fibromyalgia or chronic fatigue syndrome.14 I put silicone breast implants here just to 15 make a point. Again, most of us in the rheumatology field16 know the story of silicone breast implants. This was an 17 example where there was a false attribution between 18 symptoms and exposure. People thought that there were 19 symptoms of chronic pain and chronic fatigue and memory 20 problems and the like that were, in fact, associated with 21 silicone breast implants because there in fact were a lot 22 of women in the country in the early 1990s who had both 1 128 2 1 those symptoms and had silicone breast implants. But when2 the 14 or 15 different population-based studies that were 3 done looking at whether there was a true association 4 between breast implants and those symptoms, by and large, 5 they found that there was in fact no association, that 6 those symptoms in fact were very common in middle-aged 7 women and because there were two million women in the 8 country that had breast implants, we would expect that 9 200,000 to 300,000 of those women would have symptoms of 10 chronic pain and chronic fatigue, even if there was no 11 causal association between breast implants and those 12 symptoms.13 So for this large study that was done in the 14 VA Cooperative Trial Network that was specifically aimed 15 at improving function in returning Gulf War veterans, we 16 used the operational definition for chronic multi-symptom 17 illness. We required that people have two of three of the18 following symptoms: pain, fatigue, and memory or mood 19 difficulties. These had to begin at or after deployment 20 and still be present in the late 1990s when the study was 21 begun. I'm not going to go into all the details, but 22 basically people were randomized to receive either 1 129 2 1 cognitive-behavioral therapy alone, exercise alone, 2 cognitive-behavioral therapy plus exercise, and all four 3 groups got usual and customary care. Both exercise and 4 CBT were given in group session, not in individual 5 sessions.6 The primary outcome measure, this is what's 7 important here. Those of us who were involved in 8 designing this study thought that the most important thing9 we could do for our Gulf War veterans was improve their 10 physical function, and because there was no disease-11 specific outcome measure, we chose the physical component 12 summary scale of the SF-36 as the measure of physical 13 function that should improve. And we required a 7-point 14 improvement in the PCS to be clinically meaningful and 15 that was based on published work by Ware and others 16 suggesting that a 7-point movement in the PCS is both 17 clinically meaningful and does not occur by chance. It 18 exceeds the standard error of that measure if you give it 19 over and over again.20 Because these were veterans, the majority of 21 these people were male rather than female, but as it 22 turned out, 55 percent of the people in this trial met 1 130 2 1 criteria for fibromyalgia, 45 percent met criteria for 2 chronic fatigue syndrome. So even though these were 3 primarily males, a substantial portion of them were tender4 enough and had chronic widespread pain, so they in fact 5 would meet the criteria for fibromyalgia. They also had 6 high rates of disability and high rates of axis 1 mood 7 disorders which, as it turned out, the disability in 8 particular was a big problem with respect to showing less 9 of an effect of treatment than perhaps we otherwise would 10 have.11 I think this is really illustrative here. 12 These are the veterans in this study, the 1,100 veterans 13 who were in this study. Their PCS score on the SF-36 was 14 33.7 which is almost 2 standard deviations below the 15 population mean, and another study that was done by Lew 16 Kazis that's not published yet looking at fibromyalgia in 17 VA hospitals suggests that the average PCS score of 18 veterans with the diagnosis of fibromyalgia is 28.7, more 19 than 2 standard deviations below the population mean which20 is 50. You see here again, fibromyalgia or Gulf War 21 Illness would be significantly lower on these functional 22 status measures than these illnesses that we might 1 131 2 1 intuitively think would be lower with respect to the 2 burden that we know occurs in these illnesses.3 This study was fairly disappointing with 4 respect to the results, even though we targeted this 5 cognitive-behavioral therapy specifically to improve 6 physical function. We only showed a modest ability for 7 the CBT to do that. 18.4 percent of the people who 8 received cognitive-behavioral therapy or cognitive-9 behavioral therapy plus exercise had this 7-point 10 improvement in their PCS score, whereas 11 percent of the 11 veterans who had usual and customary care had this level 12 of improvement.13 Exercise alone led to symptomatic improvement 14 in multiple domains of symptoms and there was no 15 synergistic effect between exercise and CBT, which is 16 something again that was both disappointing and a little 17 bit surprising.18 But these are the data that are perhaps of 19 most interest to this group. When we looked at the 20 correlation between changes in symptoms and changes in 21 function in this study that was specifically done to 22 improve function, we found very modest correlations 1 132 2 1 between the improvements in PCS score over this 12-month 2 period and improvements in pain, improvements in fatigue, 3 or improvements in cognitive dysfunction. Our values of .4 3 to .4 which would lead us to think that the percentage 5 of the variants in physical function that could be 6 explained by improvement in symptoms was perhaps 10 to 15 7 percent, that is, the r squared values.8 Contrast this with the best review that I 9 could find looking at the comparable data for 10 osteoarthritis of the knee, where in osteoarthritis of the11 knee, the correlations between the different subscales of 12 the WOMAC range in the .7 to .8 range which means that 13 perhaps 50 or 60 percent of the variance in function can 14 be predicted by improvement in symptoms in osteoarthritis 15 of the knee and again the huge disparity between something16 like OA and something like fibromyalgia or chronic multi-17 symptom illnesses where there's just not nearly as big of 18 a link between symptoms and function.19 I'm not going to go through the conclusions.20 So let me just try to explain why this might 21 be. Because of this huge difference in self-report of 22 physical function in individuals with fibromyalgia, our 1 133 2 1 group and others have been very interested in trying to 2 help sort of understand or explain why that might be 3 occurring. One of the ways that you can try to get at 4 this is to actually look at objective measures of 5 activity, looking at things like activity monitors, and 6 actually try to look at how these relate to self-report of7 physical function.8 Actigraphy is actually very well validated as 9 a surrogate measure of physical activity in that if you 10 put people, for example, on a treadmill, you have an 11 actigraph connected to them, you'll find that there's a 12 quite linear relationship between what the actigraph shows13 and how many mats they're exercising on on the treadmill. 14 This actually has been extrapolated to a number of 15 different domains, and again actigraphy is fairly well 16 accepted now as being a surrogate measure of activity per 17 se. In fact, in the rheumatology literature in RA, there 18 are modest correlations between activity as measured by 19 activity monitoring and changes in the MHAQ over time in 20 individuals in clinical trials of rheumatoid arthritis.21 This happens to be the Actiwatch that we use. 22 There's a whole bunch of different ones on the market. 1 134 2 1 One of the advantages of this is that you can actually not2 only collect activity, but people can actually enter their3 symptoms as well as activities. So at various times 4 throughout the day, as we've been known to do and being 5 annoying with our subjects, is these things beep and we 6 ask them four or five times a day to record their pain, 7 record their fatigue, record their levels of stress, to 8 determine if those actually are related to activity or 9 other measures in people with fibromyalgia.10 This is an example of what an actigraph looks 11 like. People fill out a diary. You can see here that the12 activity goes up when they're doing things like running. 13 It goes down when they're doing things like sleeping. 14 Although actigraphy has actually been used as sort of a 15 surrogate measure of sleep efficiency because if people 16 are thrashing around a lot during sleep, they're not 17 getting as good a sleep as they are if they happen to, in 18 fact, be resting. But again, an average look at what 19 actigraphy will show you.20 In this particular study, we had 30 people 21 with fibromyalgia and 29 controls. The controls were 22 specifically selected to be sedentary controls, not active 1 135 2 1 exercising controls, and we were interested over this 5-2 day period not only what the activity levels were but how 3 activity related to symptoms in people with fibromyalgia.4 Now, for any of the fibromyalgia skeptics that5 might be hiding in the room here, I'm not going to leave 6 this slide up very long because this slide by itself will 7 lead people to think that fibromyalgia isn't really real.8 There was no difference at all between the 9 patients in controls in either daytime activity or 10 nighttime activity as measured by actigraphy, even though 11 there was a 20-point difference in the physical component 12 summary score in the people with fibromyalgia. So 2 13 standard deviations lower with respect to self-report 14 activity, yet no difference whatsoever with respect to the15 mean activity levels in people with fibromyalgia.16 However, what we did find is there were large 17 differences in the peak activity levels in people with 18 fibromyalgia. You see here the difference between the 19 peak activity levels as well as the standard deviation or 20 the variability of activity. What we basically found in 21 people with fibromyalgia is they couldn't raise their 22 activity. They couldn't meet different types of sort of 1 136 2 1 daily demands. So what you find in fibromyalgia patients 2 is that they didn't have the ability to go to these higher3 levels of peak activity that the normal controls did and 4 you see this here depicted. Although they were very 5 similar in the morning when they woke up, at midmorning, 6 at afternoon, and at evening, you see the much higher peak7 activity levels in the controls than you see here in the 8 fibromyalgia subjects.9 This is just actograms of the two different 10 groups, a representative fibromyalgia patient and a 11 representative control. You see in the control, all these12 high peaks where people can basically raise their 13 activity, and you see in certain days in the fibromyalgia 14 patients, there are certain hours where basically they 15 have to be sedentary. And we would find fibromyalgia 16 patients that for days at a time, they would basically be 17 fairly sedentary, then they would do a little bit the next18 day and then have several days afterwards, again leading 19 to equal means or averages between the groups but markedly20 different peaks between the two groups.21 The other fascinating thing with respect to 22 this study is that we didn't find any relationship between 1 137 2 1 either peak or average ratings of pain, fatigue, or stress2 in the patient groups. So the level of symptoms they were3 having on that particular day did not correlate with what 4 they did on that particular day, but we didn't find that 5 in the control groups either, and the same held true for 6 the fact that there was no relationship in either the 7 patient or the control groups between self-report 8 function, in this case as measured by the SF-36, and 9 between objective measures of activity in either patients 10 or controls.11 So I think what this study is telling us is a 12 couple of things. One is that what seems to be most 13 abnormal in people with fibromyalgia is sort of the 14 ability to respond to demands of day-to-day life, not 15 necessarily that they can't do sort of certain things from16 a day-to-day basis, and also that we have to really wonder17 what measures like the SF-36 and other functional status 18 measures really are measuring if they're not measuring 19 activity. What is it that we're capturing in these self-20 report questionnaires, if it's not actual objective 21 activity that it is that we're capturing?22 So to conclude, fibromyalgia patients rate 1 138 2 1 their function as being very low. This domain has been 2 very difficult to improve in clinical trials, even using 3 behavioral interventions that are specifically designed to4 improve function. I happen to agree with what Larry said.5 I think that when we give cognitive-behavioral therapy in 6 the setting of adequate pharmacologic therapy, cognitive-7 behavioral therapy will work a lot better, but that's a 8 hypothesis that needs to be tested. And the dysfunction 9 in fibromyalgia, perhaps most important to this group, is 10 fundamentally different than dysfunction in other 11 rheumatic diseases in that there's not as linear a 12 relationship between symptoms and dysfunction in 13 fibromyalgia as there is in other rheumatic diseases.14 I'm just going to talk briefly about some of 15 the other outcome measures that have been considered in 16 fibromyalgia. Patient global improvement --17 DR. FIRESTEIN: Dr. Clauw?18 DR. CLAUW: Yes?19 DR. FIRESTEIN: Can you wrap up in just a 20 couple minutes?21 DR. CLAUW: Yes. Patient global improvement 22 has been considered. It is a very valid measure but only 1 139 2 1 a couple recent studies have actually looked at patient 2 global as an outcome measure.3 Fatigue. Again, this has been looked at over 4 and over again. There are multidimensional assessments of5 fatigue that have been used. There are plain old visual 6 analog scales that have been used, and I happen to agree 7 with Fred Wolfe who has actually looked at this in depth, 8 that the multidimensional measures give you more 9 qualitative information about the type of fatigue that 10 people have, but they're not any more responsive to 11 change, that a VAS, a simple VAS is probably the best 12 measure of fatigue to use in a clinical trial.13 The same holds true with sleep. One of the 14 things that you should understand about both sleep and 15 cognitive dysfunction is that self-report measures of 16 sleep do not correlate very well at all with objective 17 measures of sleep and self-report measures of cognitive 18 dysfunction do not correlate very well with objective 19 measures of cognitive dysfunction.20 So when you are doing a clinical trial in 21 fibromyalgia, what you probably would ask people if you 22 thought that sleep and cognitive function were important 1 140 2 1 domains is ask the person whether they thought these 2 domains improved rather than trying to move towards 3 looking at objective measures of sleep, like 4 polysomnography or in the case of cognition 5 neuropsychiatric testing, because in fact you don't find 6 strong correlations between those more objective measures 7 and subjective measures, either in fibromyalgia or in 8 healthy normal individuals.9 With respect to process measures or surrogate 10 outcome measures, this is probably the only thing that I 11 will say definitively, is that although our group does an 12 awful lot of functional imaging, a lot of evoked pain 13 testing, a lot of measures of autonomic function and 14 hypothalamic-pituitary-adrenal function, none of these is 15 ready for a clinical trial. None of these is ready to be 16 used as a primary outcome measure in a randomized clinical17 trial because none of them are robust enough and the ones 18 that we can get to change in highly-experimental settings,19 like in a GCRC, can't really be extrapolated to be used in20 a large multicenter clinical trial.21 So the last slide I have here is basically -- 22 I think this is actually a relatively simple decision 1 141 2 1 because there's only really only a couple answers to what 2 should be the outcome measures in fibromyalgia. Where 3 should we set the bar?4 But if we set the bar at one place, we could 5 say this is a legitimate syndrome with a large unmet need 6 just as osteoarthritis or rheumatoid arthritis were 30 7 years ago, where there are no currently-approved drugs, 8 and what we should do in fibromyalgia is improve pain.9 Lynne will tell you in a couple minutes that 10 that's probably what patients want, to improve pain, and 11 as long as we use 2003 standards for randomized clinical 12 trials, that is, we look at minimally clinically important13 differences, we look at intent-to-treat types of studies, 14 that this might be a reasonable bar for a disease like 15 fibromyalgia. This certainly would be comparable to the 16 recent approvals for IBS drugs and migraine drugs, where 17 improvement in a single domain which was pain in migraine 18 and improvement in a single domain which was patient 19 global in IBS led to approval of drugs in those different 20 domains.21 I actually happen to agree, though. I've 22 heard Lee and Jim both say many times that we don't want 1 142 2 1 to make pain better but make the patient worse. So 2 perhaps the next level at which we could set the bar would3 be that we show that people have both a clinically 4 meaningful improvement in pain and an improvement in 5 patient global. That would ensure us that the person as a6 whole is getting better as well as their pain getting 7 better.8 And then finally, the highest bar to set would9 be to require this sort of triple primary endpoint, and 10 instead of improving function in fibromyalgia, because of 11 the fact that we know function is difficult to improve, we12 perhaps could use an ACR 20 an ACR 50 responder analysis 13 and lead to improvement in many domains.14 The last thing I'll say and I'll close here is15 I think, because I can't talk any more after I get done 16 talking now, is that what I would ask all of you to do is,17 at the end of the day, when you come up with an outcome 18 measure for fibromyalgia, think of a drug that is an 19 incredibly effective central analgesic but does nothing 20 more than improve pain, and there will be such drugs. 21 There will be drugs that are very good central analgesics,22 whether they're NMDA receptor blockers or substance P 1 143 2 1 antagonists or whatever, that are very good at treating 2 central pain but don't independently affect fatigue or 3 other domains and just ask yourself two questions.4 Number one, would fibromyalgia patients 5 benefit from this drug? And number two, would the outcome6 measures that we choose, the bar that we set, allow that 7 drug to be approved?8 There's not any such drug that's in the 9 pipeline right now that's been tested, but that drug is 10 likely to come on the scene, and again I think that my own11 personal view would be that fibromyalgia patients would 12 benefit from that drug if it is safe. And as we think of 13 these sort of multiple domains, we should look at that as 14 sort of the acid test of whether a compound such as that 15 in fact would be able to be approved in the setting of 16 fibromyalgia.17 Thank you.18 (Applause.)19 DR. FIRESTEIN: Thank you.20 We have time for one question. This time Dr. 21 Strand really did have a question or a comment.22 DR. STRAND: I had a comment about the SF-36 1 144 2 1 and its use in RCTs and its correlation. Actually in RA, 2 the PCS scores are virtually across all of our recent 3 trials are about 30, 2 standard deviations from the norm, 4 and the correlations proven in both the physical function 5 domain and the PCS scores with the HAQ on the order of .7,6 .8 and .9, and we see improvements of about 10 points.7 I think your definition of an improvement in 8 PCS score of 7 was a bit high because most of the data we 9 have now from RA and also diabetes, OA, cardiovascular-10 pulmonary disease, suggests that the domain MCID scores 11 are about 5 to 10, but that PCS being scored from 0 to 50 12 would be more like 2.5 to 5.13 I wonder whether you might have seen a little 14 bit better difference with the 5, the point being again 15 also that physical function domains are positively scored 16 in the PCS and are very low in RA and show a lot of change17 and that's ostensibly what you were looking for, change in18 your study with the vets.19 DR. FIRESTEIN: Before you answer, Dr. Strand,20 I've been asked if you can identify yourself and indicate 21 any potential conflicts.22 DR. STRAND: I'm sorry. Strand, S-T-R-A-N-D, 1 145 2 1 and I teach at Stanford. I'm a consultant and I'm here on2 my own.3 DR. CLAUW: In answer to that question, we 4 actually looked at different cut points because we were 5 somewhat disappointed with the performance, and it didn't 6 really matter in this particular trial. Using lower cut 7 points wouldn't in this trial have done any better at 8 separating the treatment groups from placebo.9 I do agree with what you're saying. In 10 retrospect, perhaps we set the bar a little bit too high 11 with respect to the 7-point PCS score.12 DR. FIRESTEIN: One last comment and then 13 we're going to break.14 DR. GIBOFSKY: Dr. Clauw, in his introductory 15 remarks, Dr. Witter asked us to think about fibromyalgia 16 either as a symptom or cluster of symptoms or as a complex17 disease state with varying clinical presentations. You 18 suggest in some of your remarks that there might be a 19 subset of patients for whom we should think of the claim 20 as a way of life, that if the magical drug came on the 21 market that eliminated the symptoms, I think you said we'd22 still be left with patients who have the disease. 1 146 2 1 I wonder if you could tease that out a bit 2 more so I can understand a little bit better about how to 3 structure the claim.4 DR. CLAUW: Well, just to be clear, I didn't 5 suggest the claim was a way of life. I suggested that in 6 a subset of people with fibromyalgia that have high levels7 of psychological and behavioral co-morbidities, which most8 of the data suggests occur as a result of the fibromyalgia9 rather than they begin with, but even an effective drug --10 again, these are sort of the classic tertiary care 11 patients with fibromyalgia that probably make up a fairly 12 small subgroup of the total universe of fibromyalgia 13 patients. But even an effective drug, if administered to 14 these individuals, might not lead to a great deal of 15 improvement in function because their dysfunction has 16 occurred in large part as a result of the fact that they 17 become isolated, they become depressed. Other things 18 other than the primary symptoms of the fibromyalgia are 19 driving their dysfunction.20 Just to be clear, the same subset occurs in OA21 and RA, it's just not nearly as large a subset. We all 22 have patients of ours with OA or RA that are on 1 147 2 1 disability, that if we give them very effective drugs, we 2 don't see as much of an improvement in their functional 3 status as we might in someone who doesn't have that 4 psychological and behavioral burden, if you will, because 5 again these are people that, in addition to the 6 underlying, in the case of RA, sort of immunobiology 7 rather than neurobiology, just making that better doesn't 8 make the entire person better.9 So, hopefully, I clarified an issue or 10 answered your question.11 DR. FIRESTEIN: Dr. Anderson, you had one.12 DR. ANDERSON: Yes. I just wanted to refer to13 your slides about effect sizes from meta-analysis and also14 ask you a question about pain.15 There seemed to be quite a large number of 16 trials done and perhaps there's data there that could be 17 used in developing response criteria for fibromyalgia. 18 The measures may be somewhat different but they fall in 19 different clusters and they're similar enough that whoever20 did the meta-analysis felt they could create effect sizes 21 for them. So I'd like your comments on that, whether they22 would be usable for this purpose. 1 148 2 1 Also, about pain. You said a lot of things 2 about how the VAS is not at all reliable and so forth. 3 However, it has in a lot of contexts been found to be very4 responsive. And you end up saying for fibromyalgia that a5 VAS for fatigue was responsive. So maybe simple measures 6 of pain could be useful.7 DR. CLAUW: Let me answer the second question 8 first. I think, as you know, there's a big difference 9 between responsive and accurate/valid. The problem, I 10 think, with VAS is not a responsive issue because in fact 11 they're responsive. The issue, especially vis-a-vis 12 diaries and things like that, is whether it's a valid 13 response on the part of the patient or whether that recall14 bias, that filter that people use when they fill out a 15 diary, when they backward fill or when they forward fill a16 diary and they try to guess what their pain -- that's more17 sort of a precision/validity issue than it is a 18 responsiveness issue.19 I did say that all of those measures, the 20 electronic measures, the paper and pencil diaries, they 21 all performed about the same with respect to 22 responsiveness in the Cypress trial. So I'm not being 1 149 2 1 critical of any of these measures with respect to 2 responsiveness. I am being somewhat critical. I think we3 just have to be circumspect about these measures with 4 respect to sort of their accuracy and their validity.5 With respect to your first question, I think 6 that we have very good data that we could use to model 7 something like an ACR 20, if the drug that was going to be8 used is a tricyclic drug. That ACR 20 might be totally 9 the wrong instrument for a different compound that's 10 acting on a different part of the central nervous system. 11 Tricyclic drugs, for example, are sedating and in fact 12 many of their side effects have to do with the sedating 13 qualities of the tricyclics. A good drug for fibromyalgia14 might be a drug that is not a good sleep drug, that is an 15 activating drug that improves fatigue and improves other 16 symptoms, but doesn't do anything at all for sleep.17 So again, if we had an ACR 20 that included 18 sleep as a domain because we were modeling after 19 tricyclics and because that was the largest effect size, 20 it might not do very well for a compound that might, in 21 fact, be a better compound but just doesn't happen to hit 22 that domain. It doesn't happen to hit the sleep domains. 1 150 2 1 So I think that's the problem with an ACR 20 2 type of responder analysis, is it would have to incredible3 flexibility to capture all the different types of 4 pharmacologic agents that might be effective in treating 5 subsets of people or subsets of symptoms in fibromyalgia. 6 Maybe there is such an instrument that could be developed,7 but I guess I wonder whether that in fact is the case.8 DR. FIRESTEIN: Before we break, I've been 9 asked if Dr. Strand can disclose for the public record the10 relevant companies for which she consults, and you have a 11 list. Would you please read the list for the record?12 DR. STRAND: I don't have it with me. I will 13 e-mail it to you. Would that be sufficient?14 DR. FIRESTEIN: She will be e-mailing it. 15 Okay.16 And then for the record, we will no longer 17 take comments from the public in order to avoid getting 18 mired in this problem for the rest of the day.19 So in that case, without further ado, we will 20 break for 10 minutes. We'll start again at 11:10.21 Thank you.22 (Recess.) 1 151 2 1 DR. FIRESTEIN: Let's go ahead and get started.2 So our first presentation of this part of the 3 discussion will be by Lynne Matallana on a patient's 4 perspective.5 MS. MATALLANA: Good morning.6 First of all, I would like to very much thank 7 the FDA for inviting me to be a part of this advisory 8 committee. I know that the patients oftentimes have a lot9 of things that they would like to include in discussions 10 of this sort, and I'm very pleased to be able to be here 11 to represent that group of people.12 I also am going to ask your indulgence as I'm 13 going to sit because I don't want to fall over. So if you14 don't mind. If you can't see me from here, wave and I'll 15 try to kind of move so that you can see me.16 In 1993, I had a laparoscopy for endometriosis17 and woke up during the surgery, and at that point on, I 18 started having very unusual symptoms. I was diagnosed 19 about two years later with lupus and later rediagnosed 20 with fibromyalgia.21 In 1997, I started an organization at that 22 time called the National Fibromyalgia Awareness Campaign, 1 152 2 1 and our original intent was just to speak out on behalf of2 the patients, to let people know that this illness existed3 and that we needed help.4 As time went by and the needs of the patient 5 community as well as the medical community became more and6 more apparent to us, we became the National Fibromyalgia 7 Association two years ago, and we now publish a national 8 magazine which some of the committee members have in their9 packets that addresses issues that are very pertinent to 10 the patient community but also to the medical community, 11 and we were very pleased that this publication has been 12 received so well by the medical professionals.13 I feel qualified to represent patients because14 I talk to thousands of patients every year through 15 Internet, through phone calls, through meetings, and I 16 also am very pleased that I have had the experience of 17 working with many of you and many of the researchers and 18 doctors. We have over 50 doctors who work with us as 19 advisors. So we have quite a bit of input from them to 20 know exactly what is going on in the clinical research 21 area.22 I've been asked to speak about the patient's 1 153 2 1 perspective, and what I will be drawing from is obviously 2 my own experiences, my own intuition, the anecdotal 3 information that I have been given by other patients, and 4 a survey.5 I, unfortunately, was only appointed to this 6 committee a couple of weeks ago, but I wanted to be able 7 to bring some type of specific information from the 8 patients. So we sent out a survey with about 20 questions9 to 16,000 fibromyalgia patients. To our surprise, in five10 days, we had 1,119 responses. Obviously, I was not able 11 to tally all of that, and so we've taken a sample survey 12 response group of about 200 people. So when I give my 13 percentages, you can know that this is a group of about 14 200 people that I am referring to.15 One of the first things I want to address is 16 the picture that you saw of the woman that looked like she17 was close to death and extremely miserable because this is18 something that most people with fibromyalgia feel at one 19 time or another in their life. We do have, obviously, 20 symptoms that wax and wane, but the majority of us go 21 through a time where we are almost completely disabled, 22 myself included. I spent two years in bed and four years 1 154 2 1 at home.2 But I feel that there is very much a belief in3 the patient community that with the right support, with 4 the right medications and treatments and with the 5 understanding that we are not crazy, that this is a true 6 physical entity, that you can improve, and I think that 7 part of the problem has been that many patients have not 8 had the support or the educational information that they 9 need in order to help improve and also have not had the 10 opportunity to try certain medications that may be now in 11 more of the experimental stages. So please keep in mind 12 whenever I'm talking that I am talking about a group of 13 people who are very distressed.14 I'd like to answer several questions in my 15 presentation today, the first being: what are the unmet 16 needs of the fibromyalgia community?17 One of the first things that we are faced with18 often is how many people have this illness. I think 19 someone quoted 4 million to 10 million which is quite a 20 deviation, and we do not have any true epidemiological 21 studies that will talk about this issue, relate to this 22 issue, look at geographic considerations, the illness in 1 155 2 1 men versus women, different treatments. Many of you know 2 that fibromyalgia patients react differently to certain 3 treatments and why is that? We obviously have our lumpers4 and our splitters who look at fibromyalgia with 5 subcategories and we need to look at that more 6 specifically.7 The other thing that I think is so important 8 and you will hear constantly from people with fibromyalgia9 is the level of acceptance of the illness. Acceptance 10 from society which includes their own families and 11 employers and friends to the medical community, obviously 12 having gone to doctors who have told them either there is 13 nothing they can do for you or there is not an illness 14 called fibromyalgia, and then also that feeling of having 15 the plague. Dr. Clauw mentioned the isolation that people16 with fibromyalgia go through, and I think that this 17 obviously then intensifies the symptoms. So with the 18 acceptance and with the education, we can probably prevent19 a lot of that isolation.20 Another concern is where to go for treatment 21 because many of the doctors do not believe in this illness22 and currently rheumatologists tend to be the main 1 156 2 1 caregivers. However, as you know with the multiple 2 symptoms that we have, many patients try to go to 3 neurologists or different types of pain specialists or 4 migraine specialists, gastroenterologists, and to have 5 these groups of people who are very unfamiliar with the 6 illness can be very detrimental. So we're also looking 7 for continuing medical education and especially at the 8 level of the family practice doctor because, as you know, 9 diagnosis of fibromyalgia does usually take anywhere from 10 two to five years. So if we could educate and help 11 doctors in the family practice arena, we could probably 12 cut the duration of time for diagnosis.13 Also, it's very exciting to see fibromyalgia 14 be taken so seriously and be moving forward at the federal15 government level. However, at the state and local level, 16 that does not seem to be the case. We recently, in the 17 state of California, worked to get a bill through that all18 it did was ask the Department of Health to recognize 19 fibromyalgia and to include it in its list of illnesses 20 that they are concerned about. Not only was the bill not 21 passed but they placed another bill in its place that was 22 approved so that the previous bill on fibromyalgia will 1 157 2 1 not even be in the record. So state and local knowledge 2 and support of this illness is very much needed as well.3 We've talked about diagnosis. As far as I 4 think most patients are concerned, they feel that the 5 tender point exam is a viable technique for diagnosis. We6 don't see too many people who have been told that they do 7 meet these standards and that we don't feel have 8 fibromyalgia. However, there is the problem with people 9 not believing. So if there was a diagnostic test which 10 was not subjective, it would help us in our plight to make11 people believe in this illness.12 Also more research. Obviously, today the 13 experts have presented so many different questions that 14 need to be answered, and with the limited amount of 15 research funding. The National Fibromyalgia Association 16 is a non-profit organization that kind of squeaks by with 17 the contributions of other patients, but we have so many 18 doctors now coming to us, asking us for funding because 19 they have viable research studies that they want to do, 20 and it's very difficult for us to not be able to have that21 funding to help them. So funding is definitely a need.22 Also, we are very thrilled with the people 1 158 2 1 over the last 20 years who have been a part of the 2 research of fibromyalgia. However, several of these 3 people are starting to retire, and it's exciting when new 4 people are becoming involved, but we'd like to see even 5 more people that have new ideas and are very much not 6 afraid to look at a possible new paradigm for the 7 causation of this illness.8 As I mentioned about the diagnosis of 9 fibromyalgia, a quantifiable test would help us in proving10 the existence of this illness and also could help cut down11 on the diagnostic time frame.12 We also are interested in looking at some of 13 these subgroups. It's interesting when certain patient 14 organizations get behind a specific type of treatment, 15 such as surgery for Chiari malformation or the use of 16 guaifenesin and some of these other things. It's part of 17 the patient group and yet it's something that needs to 18 have medical evaluation. I know that, for example, on the19 guaifenesin, that Dr. Robert Bennett has done two tests 20 which clinically prove that there is no treatment help 21 from guaifenesin. However, when we do surveying, we still22 have a large percent, usually between 4 and 5 percent, of 1 159 2 1 people who have felt that this has been the main product 2 that has helped them in relieving symptoms.3 The other thing that I think is important to 4 look at is the onset of fibromyalgia. We have at times 5 thought that it was about 40 percent of people that had 6 onset because of trauma. However, in an anecdotal way of 7 looking at this from talking to fibromyalgia patients, I 8 would say at least 9 out of 10 patients do attribute the 9 onset of their illness due to some type of physical or 10 emotional trauma, and I do think this could help us in 11 learning how to possibly prevent or understand better what12 the cause of this illness is.13 Also, the role of central sensitivity 14 syndrome. The importance of being able to identify the 15 overlapping conditions is very important because what I 16 feel, although a lot of people would like to have a 17 treatment specifically for their worst symptom, I think 18 that oftentimes patients improve if they start with their 19 easiest-to-treat symptom. So, for example, if they're 20 suffering from migraine headaches and there are medical 21 prescription drugs that help this, that even though that 22 might not be their worst problem, to look at that as a 1 160 2 1 possibility for treatment first and then work up to the 2 more difficult symptoms.3 DR. FIRESTEIN: Thank you.4 Could you make a concluding remark?5 MS. MATALLANA: Okay.6 Well, what I have here now is going into the 7 survey outcomes, and I guess what I'll have to do is just 8 kind of give you an overview as far as--9 DR. FIRESTEIN: Just a concluding remark, 10 please.11 MS. MATALLANA: Okay.12 I would agree that pain is the most difficult 13 symptom and that 68 percent of people with fibromyalgia 14 are interested in finding treatment for pain.15 Thank you.16 DR. FIRESTEIN: Thank you very much.17 (Applause.)18 DR. FIRESTEIN: Next, Dr. Wells will talk 19 about outcomes: multi-system impact.20 DR. WELLS: Thank you.21 Just as some of the previous speakers, I'd 22 like to also commend the committee and the FDA for holding 1 161 2 1 these very timely and important meetings. Also, in terms 2 of full disclosure, I'd like to indicate that I am 53 3 years old, so you can take Leslie's cognitive age curve 4 and properly place me in that curve to know where I sit.5 It's very difficult to speak after a patient 6 and a consumer because they bring a real face to the issue.7 I now have to go back and take an 8 epidemiological and statistical perspective on looking at 9 outcomes in this particular area. I'll try to do that as 10 quickly as possible, also hopefully as informative as 11 possible in that process.12 I will quickly skip through the first two 13 slides. These are the obligatory slides talking about 14 what fibromyalgia is about, also the ACR criteria.15 I will focus a little bit on the second slide,16 though, to say that there are two controversies here 17 really. First of all, there's the controversy of whether 18 we're dealing with medicalization of unrelated symptoms, 19 to a syndrome, to a defined disorder. The controversy I 20 want to talk about right now is what is the most 21 appropriate or combination, composite, appropriate outcome22 measures that we can select to look at this issue. 1 162 2 1 Now, to do that, I'm going to follow the 2 following road map, and as I said, this is going to be 3 very at times statistical, so I'll quickly go through some4 of these.5 First of all, I want to give you an 6 unsystematic review of the types of outcome measures that 7 are used in fibromyalgia.8 Second of all, I want to give you an intuitive9 feel for why we choose certain measures.10 Next, the development and selection of 11 outcomes. I do want to talk about issues, such as 12 reliability, validity, sensitivity, which are very 13 important, and people often confuse the terminology, so we14 have to be careful there.15 We then are going to look at some overall 16 response criteria. How can we go about this?17 Next, the minimal clinically-important 18 difference. I'll try to put a little bit different face 19 on that rather than just giving you the definition but 20 also try to put it in context.21 And then finally, something called low disease22 activity state. Earlier, we heard about ACR 20, 50, and 1 163 2 1 70. I suggest to you that if you're going to do 2 something, you might as well as leapfrog and just not 3 repeat what someone else has done but think further down 4 the road and think of what the next step is, and I'm going5 to say to you that the next step is to look at entities 6 called low disease activity states.7 First of all, types of outcomes. This is my 8 unsystematic review. I looked at three systematic reviews9 in the literature. Two of them were in the Cochrane 10 Collaboration Review 2003 and 2002. I also looked at the 11 review by Rossy in the Annals of Behavioral Medicine in 12 1999 and took a look at some of the outcomes that they 13 viewed. I put them into different constructs, if you 14 wish, and I found eight different areas, and I could add 15 more. I could have added the economics and so on and so 16 forth. But these are the eight.17 When I look in pain, I can see everything from18 visual analog scales to ordinal scales to pain drawings. 19 I also found a very interesting article by Fred Wolfe on 20 looking at regional pain scales where he's trying to take 21 a more quantitative look at this issue.22 In tender points, we have the pain threshold 1 164 2 1 and tenderness to thumb pressure.2 In physical function, there is a host of 3 different things we can look at. We have self-report of 4 physical pain, the FIQ which Dan talked about, also the 5 fibromyalgia HAQ which is the newer scale that was 6 developed by Fred Wolfe. We also have musculoskeletal 7 performance, various ways of measuring that, 8 cardiorespiratory fitness and various ways of measuring 9 that.10 In terms of global well-being, we have the 11 physician-rated things. We also have the overall score of12 the FIQ.13 In terms of self-efficacy, there's the 14 Arthritis Self-Efficacy Questionnaire.15 In terms of fatigue and sleep, the FIQ Fatigue16 Subscale, the sleep VAS.17 Psychological function, subscales again of the18 FIQ for depression and anxiety, but remember what Dan 19 said, it was basically a visual analog scale and it wasn't20 really potentially tapping into all aspects.21 Quality of life and generic functional status,22 Short Form 36, Sickness Impact Profile, and the HAQ, if 1 165 2 1 you wish to view the HAQ as being more generic in this 2 area.3 Just to give you the background to the 4 Fibromyalgia Impact Questionnaire, it's a brief 10-item 5 questionnaire. It measures a number of physical functions6 which are up there on the screen. It was developed in 7 1991 by Bennett. Basically, the questions are were you 8 able to do some of these particular activities, and as was9 indicated earlier, many of these activities, people would 10 not respond to today in terms of, for example, of washing 11 dishes and so forth. There's also nine other questions. 12 All of a sudden, I noticed it's changed to dots instead of13 numbers, but anyway, there's nine other questions and some14 of these questions are very specific, for example, to 15 people who actually work. So you're going to find a lot 16 of missing information. This is one of the reasons why 17 Fred Wolfe in 2000 developed the FHAQ and he compared one 18 to the other because he felt that some of these items 19 would be missing too often for the FIQ to be useful and 20 also some of the items would not be applicable today.21 Now, choosing outcomes. Okay. First of all, 22 just generalities. We like objective measurements. We'd 1 166 2 1 like to, if we could, reduce or reverse disease. We'd 2 like to improve quality of life. We'd like to reduce 3 mortality. We'd like to have a good global impression, 4 both in the patient and the physician. We'd like to 5 improve symptomatology, and we'd like biochemical 6 measures, if that was possible.7 Now, from the patients, what do the patients 8 want? To live as long as possible. That's your first D, 9 death. To be normally functioning, so getting away from 10 disability. To be free of pain, psychological, physical, 11 social, and other symptoms, discomfort. To be free of 12 problems from treatments, drugs, side effects, and so 13 forth, and to remain solvent, the other D which is 14 destitution, if you have to pay for some of these 15 disorders. This is what the patient wants, just very 16 globally what they would want.17 There are other ways of identifying best 18 outcomes, and let me just going to focus for a couple of 19 seconds on what influences the physician's decision. The 20 outcome measurements. This is a study that was actually 21 done by Nick Bellamy in 1998 and 1999, and he asked the 22 question: how often do you serially use the following 1 167 2 1 assessment techniques for longitudinally monitoring the 2 efficacy of antirheumatic drug therapy in your adult 3 fibromyalgia and patient practice? He did Canada and he 4 did Australia. Take a look at this. The quality of the 5 sleep is usually and always of importance. Fatigue, 6 usually and always of importance. The number of tender 7 points, important but not as important, and skinfold 8 thickness, not important at all, relatively speaking.9 In Australia, when he did the study the 10 following year, he didn't include skinfold thickness, just11 stuck with the other three outcomes, and they all 12 reflected something similar, except maybe a little bit 13 less in terms of being "always" for the Australians.14 So let's look at the development and selection15 of outcomes, and this is where I'll try to go through 16 quickly so that we can save some time.17 We have to look at the comprehensiveness or 18 the content validity. We have to know that we've included19 the proper components of health. We have to look at 20 credibility or face validity. What appears to be sensible21 and interpretable is there. We have to look at accuracy. 22 Does it reflect the true clinical status of the patient? 1 168 2 1 We have to look at sensitivity to change and also 2 biological sense as a construct validity.3 So the three key measurements are reliability,4 validity, and sensitivity to change, and it would be nice 5 to take all the various outcomes that are around and take 6 a look at their reliability, validity, and sensitivity to 7 change. I'm going to go through a little bit of details 8 on these, just to give you a sense of what each of these 9 involves. The terminology that's used in this area is 10 often not used properly, so we might as well get it 11 correct right now.12 Reliability is the reflection of the amount of13 error, both random error and systematic, inherent to any 14 measurement. It determines who reproducible the scale is 15 under different conditions.16 The reliability coefficient expresses the 17 proportion of the true variation that you would see which 18 is due to the subject's variability and not due to this 19 measurement error. Reliability can either be 20 reproducibility or internal consistency.21 We use reproducibility when we want 22 test/retest reliability to look at intra- and inter-rater 1 169 2 1 reliabilities, which is very important for measure, or 2 internal consistency if we have a scale and we want to see3 how consistent the items are within the scale. Some of 4 the coefficients we can use for reproducibility are the 5 intra-class correlation coefficient, the Pearson's r, 6 we've seen a few of those this morning, Kendall's Index, 7 kappa coefficient, and Bland and Altman plots.8 Other considerations. If the test is always 9 done by the same observer or if the test has different 10 observers, then you've got to pay a bit of a price by 11 putting that component in the denominator. So that's 12 important when you're evaluating reliability.13 Also, observer nested within the subjects. So14 if several subjects are being evaluated by several 15 observers, you must take that into consideration. You 16 must use the right statistical techniques, in this case 17 ANOVA, to do that.18 You could have multiple observations on an 19 individual, either because you've got several items on a 20 questionnaire, several observers, a repeated use of an 21 instrument, and again you have to accommodate that in your22 coefficient. 1 170 2 1 Internal consistency essentially means that 2 are all the items that you're looking at within the scale 3 agreeing with one another, are they going roughly in the 4 same direction, and you would like to see correlations of 5 that nature. Correlation coefficients could be item 6 total, split-half, Kuder-Richardson, Cronbach's alpha. 7 These are all standard ways of looking at internal 8 consistencies.9 We can improve reliability by reducing the 10 error variance through good training, increase the true 11 value by adding items, provided the items add information 12 and just not replicate information.13 Validity. The degree of confidence we can 14 place on inferences being made on the scores in the scale.15 We have something called content validity, so 16 to cover all the domains of interest. When we look at a 17 particular instrument, we want to ensure that patients and18 physicians are comfortable that the key components are 19 being covered.20 Then we have criterion validity which 21 basically means we have a gold standard, a criterion which22 we can compare things to. 1 171 2 1 We also have construct validity. Construct 2 validity is there's no gold standard but we're looking for3 circumstantial information, if you wish, and we look for 4 situations where the instrument that we're looking at 5 should correlate with other methods and does it, or 6 divergent, whether the instrument we're looking at should 7 not agree with something and it doesn't.8 So we have criterion validity where you have a9 gold standard, and we have construct validity where you 10 base everything on circumstantial evidence. These two 11 concepts are constantly misinterpreted.12 There's other more sophisticated ways of 13 looking at construct validity through factorial analysis 14 and multi-trait/multi-method analysis, and I won't go 15 there.16 To evaluate validity, we do it with 17 correlations. We do it with receiver operator curves, and18 we can do it with using 2x2 tables on sensitivities and 19 specificities.20 Sensitivity to change. So this is the third. 21 We've gone through liability. We've gone through 22 validity. Now sensitivity to change. What is the ability 1 172 2 1 of an instrument to detect small but clinically important 2 differences? That's what we're after. We can use three 3 types. There's many types of measures. We could just 4 simply do a t-test that compares baseline to follow-up to 5 see if things have changed. We can use an effect size 6 which is basically the difference of the mean and the 7 follow-up at baseline to the standard deviation, or we can8 use an ROC curve. So there are different ways of looking 9 at sensitivity to change.10 I'm going to take the FIQ just to go through 11 an exercise. It's the one that's been around since 1991 12 and you can see maybe some of these reliabilities, 13 validities, and responsiveness to change in action. When 14 they developed this instrument and published it, they said15 they had test/retest reliability because they looked at 16 Pearson r correlations, and on repeated measurements 17 between raters, they got between a .56 and a .95 Pearson 18 relationship.19 Content validity. They assessed the percent 20 missing data, and this is really a concern because 11 21 percent did not answer the washing by hand, 20 percent did22 not answer the yard work, and 38 percent did not have jobs 1 173 2 1 or did not work outside the house, and so those questions 2 could not be answered as well.3 They looked at construct validity by comparing4 it to the AIMS in different items and scales, such as 5 physical functioning, pain, depression, anxiety, and the 6 values were not too bad. They also did a correlational 7 analysis by looking at specific measures of the AIMS 8 Impact Analog and Syndrome Activity and Tender Points and 9 found for the various items some very, very low 10 correlations and in other cases high, so it was quite a 11 range, and they did a factor analysis which also proved to12 be not too bad.13 They looked at responsiveness to perceived 14 clinical outcome. It was done in a paper published in the15 Journal of Rheumatology in 2000. You can see that as an 16 individual patient perceived, they went from improved to 17 unchanged or worse. The FIQ did go in the right order as 18 they indeed got worse, as the patient perceived they were 19 getting worse. But Fred Wolfe, when he talked about the 20 FHAQ, did note that the FIQ systematically underestimates 21 the functional impairment because it doesn't handle 22 activities not usually performed by the patients filling 1 174 2 1 the form out.2 6-minute walk in 2000. It was found when they3 looked at the 6-minute walk in the group who were before 4 and after exercise, that they did find a statistical 5 change in the 6-minute walk. They didn't find that the 6-6 minute walk was highly correlated with PVO2, so it wasn't 7 doing a very good job as a valid predictor of 8 cardiorespiratory fitness. They did find, though, that it9 was highly related to the FIQ. So the 6-minute walk had 10 some nice properties but it didn't really pick up on the 11 cardiovascular, although it was responsive to change.12 I won't go through this generic versus 13 specific. I'll skip that.14 Overall response criteria. So now we have a 15 set of outcomes, outcomes that may be reliable, outcomes 16 that may be valid, and outcomes that may be sensitive. 17 And the question now as we're dealing with something 18 that's multidimensional: is there some way that we can 19 bring them together into a response or an improvement 20 criteria? I'm going to give you the five steps. Again, 21 those dots really aren't dots, they're numbers.22 The first dot is number 1, where you would 1 175 2 1 look at the outcome measures and you would look at all the2 various outcome measures that are used in the area that 3 the patients, the physicians, and other stakeholders are 4 interested in. You would look at the reliabilities, the 5 sensitivities, and the validity issues. I quoted some 6 papers there, but there are a lot of other papers that 7 have been published over the last 10 to 12 years on some 8 of these measures and some of those properties.9 You would then conduct a survey of physicians.10 You would provide them with information on randomly 11 selected patients from clinical trials and the thresholds 12 of what you think would be improvement. So basically you 13 would take for outcome measures of interest, you would 14 take data at the baseline. You'd take data at the end of 15 the study. You'd take percent change provided for each 16 patient. You would survey the clinicians and having them 17 indicate whether they felt the patient was improved on the18 basis of the profile that you provided them with on the 19 core outcomes that you're interested in, and then the 20 analysis would then focus on the patients characterized by21 the vast majority as having improved.22 Once you did that, you would do a statistical 1 176 2 1 analysis of the clinical trial data for selecting 2 definition of improvement, and this is the point where we 3 would like to assemble appropriate placebo-controlled 4 trials with very efficacious. I put "very" in quotes 5 here. It obviously depends on the particular disorder 6 you're looking at, and that also included the measures 7 you're interested in. So the improvement criteria 8 selected that best discriminates the efficacious 9 intervention from the placebo would be further evaluated. 10 You would evaluate them in large comparative data sets and11 then, finally, you do have to subject them to kind of that12 face validity evaluation at the end of the day. So again 13 we take all the core measures that are reliable, 14 sensitive, valid, of varying degrees, come up with a core 15 set, evaluate them in the data sets, survey the 16 constituencies.17 This is an example of one -- and I'm going to 18 go through this very quickly -- that actually Simms and 19 David Felson were involved with in 1991, taking 20 preliminary criteria for response to treatment in 21 fibromyalgia. They did look at a clinical trial where 22 there appeared to be an efficacious difference. They took 1 177 2 1 the treatment to be the proxy measure for response. So 2 everybody in the active treatment was considered to be a 3 responder, everybody in the other was not. They had 4 outcome measures that included physician global, patient 5 global, pain, fatigue, sleep, tender point score. They 6 then used a number of statistical techniques to look at 7 various combinations of outcome variables that they then 8 subjected to receiver operator curve evaluation to find 9 out the optimal sensitivity and specificity. They then 10 applied these to an unreported trial.11 Now, what they came out with at that time was 12 a criteria that included physician global assessment was 13 less than or equal to 4. You can see the scale being 0 to14 10, from well to poor. Patient sleep, less than or equal 15 to 6. Tender point score less than or equal to 14. The 16 most important point that they made in the paper was that 17 as more sensitive and clinically relevant outcomes are 18 developed, you can apply this methodology, which is really19 a working action of what I described in theory a little 20 earlier, to refine the criteria or to develop more 21 criteria.22 Minimal clinically important difference. It 1 178 2 1 will be so easy for me to in two sentences tell you what a2 minimal clinically important difference is and then move 3 on and you'd have no concept any further than that. I'm 4 going to try to put it in a little bit of a context. I'm 5 going to go through this relatively quickly because it's 6 really to the side of the types of issues that we want to 7 deal with.8 I'm going to give you minimal clinically 9 important differences in terms of what are called studies 10 of responsiveness. This is going to be a classification 11 system on how we can put studies that look at 12 responsiveness into context. I'm then going to tell you 13 about a systematic review that we did looking at the 14 various methods for minimally clinically important 15 differences. This is very key to, obviously, evaluating 16 various pharmacological and non-pharmacological treatments17 for this disorder.18 Studies of responsiveness essentially are 19 studies that evaluate the ability of an outcome measure to20 accurately detect change when change has occurred. Each 21 study defines the change. It can define it according to 22 three key features. Is the change for an individual or is 1 179 2 1 the change within the group? Which data is being 2 compared? Are we interested in data that's within a 3 group, between groups, or looking over time? What kind of4 change is being quantified, of which one of those changes 5 will be the minimally clinically important difference?6 So the setting is who's the focus? Group or 7 individuals? Which scores are being contrasted? 8 Differences between groups, changes within groups, or 9 both, meaning that you're going to be looking at different10 scores between two different groups, or what kind of 11 change? It goes all the way from minimally potentially 12 detectable to detectable beyond error to observed in the 13 population, something that's estimated to have changed as 14 something that is important and estimated to have changed,15 and that's your minimal clinically important difference.16 These three features all can be put at right 17 angles to one another and then you could have this type of18 system. So the setting is the individual or the group, 19 what are you looking at, differences between, within, or 20 both, and then the type of change that you're doing.21 Now, what's nice about the cube is that we can22 take a study of responsiveness and we can look in 1 180 2 1 particular at minimal clinically important differences and2 see where the holes are in the theory, see what's 3 available to us when we wanted to apply it to such a 4 problem that we're dealing with today. So let's take a 5 look at that survey, and we're going to put it inside the 6 cube.7 So an MCID is considered as the smallest 8 change or difference in an outcome measure that is 9 perceived as beneficial and will lead to a change in the 10 patients' management, assuming an absence of excessive 11 side effects and costs, and that would be the two-line 12 definition I would give you if I wasn't going through this13 process. We wanted to consider the different ways that 14 people try to derive MCIDs and look at the different 15 methods. We did the literature search. We read the 16 articles, in particular the methods sections, and then we 17 categorized it according to the cube, and this is what we 18 ended up with.19 On the right-hand side, you can see different 20 types of methods appearing. There will be a little window21 here that's going to give you a three-step process of how 22 it was done and then it's going to be dropped into these 1 181 2 1 cells and what you're going to find is that most of the 2 methods fall in this area which is basically that they're 3 looking at groups. They're not looking at individuals. 4 They're looking at groups and the changes within those 5 groups to define minimal clinically important differences,6 whereas we should really try to look within the 7 individual. The methods may be more sensitive. So I'll 8 just click away and you'll see.9 So the first one is looking at patient 10 perspectives, and it actually falls as changes within but 11 within a group.12 The next one is patient conversation. Again, 13 it's looking at a group.14 Clinical perspectives. We have two more, two 15 different ways of looking at it, both of them comparing 16 groups.17 Clinical perspective again, patient scenario, 18 comparing groups.19 Patient scenario comparison, two different 20 ways of looking at that but again within groups.21 Finally, we get one that looks at the 22 individual which is called a prognostic rating scale, a 1 182 2 1 data-driven approach, discerning important improvement, 2 improvement criteria, and then finally achieving treatment3 goals.4 Again, these are the ways that you do it. 5 These are the different methods that were there.6 The bottom line of this whole process is that 7 we do a lot with groups. We do not do enough with 8 individuals, and we need to develop more important 9 measures in that direction. So again, within this area, 10 if we can develop that within some of these measures as 11 opposed to falling back on old technologies.12 Low disease activity state. This is a 13 relatively interesting concept, boring from trying to 14 control hypertension. If we can keep blood pressure 15 within a range that both the physicians and the patients 16 are happy about, then we consider that we're in kind of a 17 steady state. We're not looking at remission or anything 18 like that. We're just saying that I'm happy where the 19 patient is at, the patient is happy where he or she is at,20 and we feel that we have everything in control.21 So we've had workshops on this and to meet 22 many of the challenges that exist in trying to determine 1 183 2 1 what we mean by low disease activity state, we've been 2 concentrating in the area of rheumatoid arthritis, but 3 this is where I'm saying that we should be a little bit 4 more forward thinking and think about this as we're 5 thinking about the responder criteria.6 So the working definition is that it is a 7 state that is deemed a useful treatment target by both 8 patients and physicians. That's what our working 9 definition of a low disease activity state would be. At 10 this particular workshop, we obtained a large number of 11 research agenda, all the way from looking at some of the 12 core criteria within the core set for rheumatoid arthritis13 to including fatigue and sleep within that criteria, and 14 then the one I have highlighted is to design and conduct 15 an opinion-based and observation approach for determining 16 a low disease activity state for rheumatoid arthritis. So17 if you wish, this is going beyond the ACR 20. Then we 18 wanted to finally then design and conduct a survey on how 19 we should present this.20 So in terms of the design and conduct of an 21 opinion-based system, the steps are as follows. The 22 opinions of the physicians and patients will be collected. 1 184 2 1 Based on these opinions, we'll come up with candidate 2 definitions. They'll be composed and they'll be tested in3 data sets. The results of this work will be collated and 4 circulated to workshop participants, and at the workshop, 5 we'll sit and we'll argue about it, both in plenary and in6 small group sessions, and probably come up with a number, 7 hopefully a limited number, of top candidates that can 8 then be validated in the following steps.9 And Chair, I think that that's the end of the 10 presentation.11 (Applause.)12 DR. FIRESTEIN: Are there any questions or 13 comments for Dr. Wells? Yes?14 DR. TURK: Thank you for the presentation.15 I wondered if you'd care to comment about 16 norms, which you didn't seem to pay any attention to at 17 all, as a lot of the measures that are available were 18 never developed and standardized in the appropriate 19 populations. Do you have any comment about that?20 DR. WELLS: Yes. In particular, if you went 21 with something, such as the -- I mean, if a measure has 22 been properly developed, let's say the SF-36, where it's 1 185 2 1 been normed to the particular population, so you can look 2 at the deviation from the norm, I think a lot of the 3 measures that we look at have not been and should be. I 4 agree.5 DR. FIRESTEIN: Thank you very much.6 The next section was the open public hearing, 7 but since there were no requests for time, we're then 8 going to move on to Lee Simon who is going to charge us 9 with something.10 DR. SIMON: First, I have to get my computer 11 to work. So I hope you'll indulge me for one second.12 (Pause.)13 DR. SIMON: Well, as it's coming up, I'd like 14 to first thank the committee members for arriving here and15 bringing this on, as Dr. Witter noted. We are greatly 16 appreciative of you taking your time out of your busy 17 schedule to help inform us at the agency about this 18 incredibly complicated arena.19 Secondly, I'd like to take the opportunity as 20 the first one at the end of all these invited speakers to 21 say how grateful we are that you all came under sometimes 22 unusual circumstances to give us your opinion about this 1 186 2 1 particularly controversial area.2 As Dan Clauw noted, I come from a different 3 background than typically seen in the context of the 4 fibromyalgia background. Having been at the bench for 15 5 years, I'm a little driven by evidence and I tried to be 6 able to apply that over the years, and as a clinician, 7 seeing patients for 25 years, always became very 8 frustrated about seeing patients with fibromyalgia.9 I think that the world has turned, however, 10 and there seems to be a significant amount of science that11 is the underpinning of an understanding of what's really 12 going on here. So everyone has mentioned the uniqueness 13 of the moment, and it does appear that there's a bunch of 14 things that are all coming together that allow us to 15 finally begin to deal with this and give it the attention 16 that it truly deserves, considering the number of people 17 that have suffered with this disorder for such a long 18 period of time.19 You'll notice that I actually have changed my 20 picture on my desktop. This is now a storm, and I 21 actually kind of feel like I'm in the midst of a storm in 22 my continuing career at the FDA. It's really quite 1 187 2 1 appropriate and also almost very appropriate for this 2 particular discussion.3 So what are the challenges in the development 4 of the therapies for fibromyalgia? You've spent a 5 significant amount of time actually looking at that 6 particular question, and I'd like to point out a couple 7 things historically, in addition to what you've already 8 heard. In fact, however far we've come in understanding 9 and divining the description of disease states and 10 increasing the understanding of the biology of pain, the 11 drugs that are presently available for chronic pain are 12 basically the same drugs we had a hundred years ago. I 13 point out that opioids, non-steroidal anti-inflammatory 14 drugs and the congeners, sedatives, muscle relaxants, are 15 those things that are still being used, and clearly that 16 is just not adequate for our present understanding.17 You've heard already that pain clearly is 18 real, but it is also subjective. I've mentioned before in19 circumstances like this that in fact I need to be put to 20 sleep to have my teeth cleaned, whereas my wife gets her 21 teeth worked on with no novocaine. She claims that she 22 has no pain. I walk into the dentist's office, my heart 1 188 2 1 is racing, I'm sweating, and they haven't even touched me 2 yet. So everyone learns the meaning of pain through 3 experiences usually related to injuries in early life, and4 some unpleasant experience or sensation becomes an 5 emotional experience a la my childhood experiences with a 6 dentist.7 Pain is a significant stress physically and 8 emotionally and you've heard much about what stress might 9 do to certain genetic hosts that might lead to an 10 establishment of a disease, such as fibromyalgia. So 11 looking at ways to define chronic pain, and we've heard 12 some of this but not all of it, we turned to the Merck 13 Manual in 2002, the Centennial 17th Edition. In this 14 edition, chronic pain is defined broadly and arbitrarily 15 as pain which persists for greater than one month beyond 16 any acute injury, and in this context of fibromyalgia, we 17 may need to think about the acute injury as a stressful 18 event. Perhaps it was going to the Gulf War in 1991, 19 perhaps it is learning that your Medcat scores are not as 20 good as you'd like.21 Persistent and recurring pain for at least 22 three months and pain expected to continue or progress may 1 189 2 1 be associated or not associated with ongoing tissue 2 injury. It has no adaptive role. It doesn't help one to 3 survive. You just suffer with it.4 And vegetative signs and depression may 5 follow, and we've heard some of those issues, and in fact,6 Art Lipman has gone along and suggested in this construct 7 that I'm going to show you that the psychosocial component8 must be dealt with before depression becomes part of the 9 clinical picture. Chronic pain should be recognized as a 10 multifactorial disease state, requiring intervention at 11 many levels, and he pictures it like this.12 You heard from multiple speakers this morning 13 that once it's happening and a patient is seen with this 14 particular scenario in a tertiary care setting, it almost 15 may be too late, that basically the construct that they 16 presently are dealing with is just untreatable in the 17 context of even alleviating their discomfort. So finding 18 these patients earlier on, perhaps in a primary care 19 arena, may allow us to obviate the eventual onset of some 20 of these things as drawn here, where here is the 21 pathologic process interacting with the physical factors, 22 then going up the scaler over time, leading to 1 190 2 1 psychological events, anxiety, depression, hostility, 2 loneliness, thus isolation and those other social factors 3 that play a role. Clearly, as you can see in this 4 reference, this is for cancer nursing, but nonetheless can5 be easily applied to this particular scenario.6 In addition, we at the agency have been 7 grappling and have had some significant energetic debates 8 with other divisions within the agency about how to 9 describe chronic pain. We can think of lots of different 10 ways and one of the really important ways is a la the 199211 Pain Guidance document which, for those of you that are 12 interested, we've actually applied for it being removed 13 from the docket so that people can't use this any longer.14 What we are looking at here is the concept of 15 mild, moderate, and severe pain. We all use this kind of 16 jargon when we talk. We all kind of apply this in both 17 talking to our patients and trying to understand ourselves18 suffering a particular injury and what it would mean. The19 problem, of course, is it's extraordinarily subjective. 20 It's descriptive but does not provide rigor. Perhaps 21 these should be used to modify the concept of chronic pain22 indication to allow patients to understand, but I'd like 1 191 2 1 to challenge the committee to help us understand how you 2 measure what is mild or moderate to severe. It's the bias3 of us as the agency to determine what might be that 4 particular definition. It's the bias of the 5 investigators. It's the bias of the sponsors that are 6 developing the therapeutics, and of course, most 7 importantly left off of here is the bias of the patient. 8 How in the world can we determine what any one person 9 thinks is moderate or severe or mild? Perhaps it's partly10 related to how they function, and of course function has 11 already been overwhelming trashed repeatedly by many of 12 the speakers as being something that's particularly 13 applicable to understand this particular scenario.14 So in thinking about fibromyalgia, we've heard15 a lot about the symptoms associated with fibromyalgia. 16 We've thought about and heard about the fact that there 17 are components of the disease, but in fact is fibromyalgia18 a painful syndrome with pain as we've heard from even the 19 patient as the critical nature of the measure that should 20 be looked at to determine outcome, but in fact is the 21 disease a neuroendocrine disorder and pain just the 22 primary or most important manifestation, or is it a 1 192 2 1 painful condition with a neuroendocrine disorder 2 associated with it? Is wind-up an epiphenomenon or is it 3 causal, and if it's causal, is it important to measure? 4 And if it's important to measure, can we use it as an 5 indication for an outcome that you alter wind-up? Will 6 that then change the fundamental chronic process that then7 would lead to not having chronic pain?8 So that would take us to a concept where we 9 ask this question. Internally, we've had the debate 10 whether I should even ask this question of the committee. 11 Is this improvement in the pain of fibromyalgia or is this12 improvement in fibromyalgia? It has enormous implications13 because one is dealing with the syndrome of fibromyalgia 14 and perhaps its improvement, the other is dealing with 15 just a painful state, one component of that. You may be 16 able to measure a change, but is that actually improvement17 in the whole scenario?18 So many of you have seen these kinds of 19 scalers before, and we have typically in the agency, at 20 least in this division, thought about the concepts of 21 what's important for pain domains, not to exclude all of 22 these, but to actually think that these are the critical 1 193 2 1 ones where you measure pain relief, pain-related function,2 and patient global. You heard this from Dr. Witter. You 3 heard this from others this morning. Clearly, all these 4 other things are very important, but what are the primary 5 ways that one would determine a primary outcome?6 So in looking at that context, we have seen 7 these lists. Pain, patient global, health-related quality8 of life, and physical function measures, we believe are 9 critically important in thinking about this as a scenario,10 as a syndrome, not just the pain of. However, obviously 11 it's also important to know that perhaps these get better 12 or at least do not worsen in the context of interventions.13 How to measure of these becomes important, and then 14 listening to three of the last speakers, I would even go 15 so far as to wonder whether or not we should be thinking 16 about perhaps just one of these measures at any one time 17 could be enough, as long as everything else didn't worsen,18 as we begin to learn more and more and more about critical19 measures associated with this particular scenario.20 And then, obviously we don't want to ignore 21 what Dr. Witter reminded us about, which is the 22 mechanistic claim. Having heard some of the issues that 1 194 2 1 Dr. Crofford brought up, there are so many different ways 2 to be able to think about this in the context of the 3 science that now could be measured, perhaps now we can 4 begin to apply the mechanistic claim to some subsets of 5 patients with fibromyalgia. So measuring an alteration in6 NMDA activity, which then might prevent wind-up, if that 7 construct is true, may be important. Maybe it's important8 in some patients to reduce prostaglandin levels that you 9 can actually measure either in the CSF or some other 10 methodology that would be applicable, perhaps an imaging 11 methodology that would be appropriate, other measurable 12 biologic changes in chronic pain states that have not yet 13 even been defined.14 At one of the meetings that we participated 15 in, Cliff Wolf presented extraordinary evidence in the 16 animal about an acute and chronic pain scenario, about up 17 regulation of 700 and something genes in the spinal cord 18 and down regulation of 545 genes. Clearly, the animal is 19 expending significant resources in these changes and 20 that's probably important. What those changes are and 21 what they represent elude us still, but that doesn't mean 22 we shouldn't be looking at them. 1 195 2 1 And then, clearly we have another recurrent 2 theme that comes up to us, which is, well, if you're 3 actually going to be able to measure change in these 4 chronic scenarios. Patients are not typically coming to 5 these to get therapy without having already been on 6 something, and thus could you measure a change in what 7 they have been on, suggesting that in fact that's an 8 improvement. In rheumatology, that has been traditionally9 looked at as glucocorticoid use, meaning you decrease the 10 use of glucocorticoids, thus you're making improvement, 11 perhaps if you decrease the use of non-steroidals or 12 decrease the use of opioids in a measurable clinically 13 important way, and that might be an important measure for 14 a primary outcome.15 Dr. Witter showed aspects of this slide, the 16 ideal characteristics of a pain metric, and I want to 17 remind you as we begin to grapple with this that we need 18 to think about it in the context that it's easy and 19 understandable by patients and clinicians. We've been 20 struck by the fact that most clinicians don't read the 21 label which is embarrassing since what the FDA mostly does22 is define itself by what's in the label and that's 1 196 2 1 unfortunate. There's a lot of interesting material in the2 label.3 And clearly whatever we use as an outcome 4 needs to be able to be explicable within that construct. 5 It needs to be applicable across studies. Therefore, many6 studies are done to help establish what you're going to do7 for pivotal trials and under those circumstances, we need 8 to be able to use these outcomes to facilitate full 9 development, and as Dr. Clauw suggested, perhaps imaging 10 of the brain is not something that's going to be 11 applicable for a full drug development program as opposed 12 to a proof of concept.13 It defines a clinically meaningful result. 14 It's valid, and I'm using the term "valid" in the context 15 of what Dr. Wells suggested. And it measures response, 16 again as per Dr. Wells, in a variety of pain conditions 17 and therapies, and it's achievable with current meds. I 18 would like to suggest, however, that that might be a wish.19 It may well be that the current meds that we're talking 20 about are just around the corner and we need to be 21 flexible to understand how to measure these particular 22 outcomes. And it should be tiered to define important 1 197 2 1 differences in drugs.2 So we heard about this issue about choosing 3 measurements of response and how it was done, and I'd just4 like to point out that in our division, there are two 5 different models in the context of that, the OA model, the6 RA model. The OA model, which is a model of chronic pain 7 which is used and applied by our division, is mostly a 8 local disease and presently requires these three co-9 primary outcomes for approval, the VAS scale for pain, 10 WOMAC for function, and a patient global, and all three 11 must win; whereas, the RA model, which is a systemic 12 disease which may have local symptoms, is actually 13 measured through a responder index and you actually saw 14 the outcomes of this responder index.15 I'd like to point out one particularly 16 important aspect of this responder index is that in the 17 first cut point here is tender and swollen joint counts. 18 I'd like to point out that this was designed with lots of 19 clinicians in mind, and we have learned something. What 20 we have learned is that physicians like to believe they 21 have an important impact on the measurement of outcome. 22 Thus, the ACR 20 is actually somewhat sullied by this 1 198 2 1 particular measure because the cut requires the physician 2 input and then in fact these are the ones that are 3 subjected to this particular outcome. I'd like to think 4 that we've moved along here and recognize that patient-5 reported outcomes are equally as important as are the 6 physician observations and thus maybe we should be 7 thinking, if we're thinking about a responder index, that 8 we don't distinguish the importance between the two and 9 not think of a cut point in one versus another.10 So also thinking about inclusion and exclusion11 criteria, in thinking about the homogeneity versus 12 heterogeneity of the disease, one has to ask the question:13 so, if we're going to try to get real good outcome 14 measures and we're going to apply them in a patient 15 population that seems similar, should we think about the 16 fact early on or later that patients who have a prominent 17 component of depression should be excluded or should be 18 included? And then, if they are included in the trial, 19 how do we handle the antidepressants that are used that 20 actually might have an impact on the outcome of 21 fibromyalgia per se, and how do we control for that? Do 22 we tier it? Do we stratify? How do we handle that? 1 199 2 1 Should we include -- and Dr. Crofford and others have 2 actually mentioned this this morning -- the patients that 3 have secondary fibromyalgia, whatever that might mean? I 4 don't mean to actually codify a scenario of primary and 5 second, but we all know there are patients who have a 6 disease as a stressor leading to symptoms of fibromyalgia,7 and thus do we treat rheumatoid arthritis patients who 8 have fibromyalgia and then treat the rheumatoid arthritis 9 and find that their fibromyalgia gets better, thus the 10 treatments for rheumatoid arthritis should be approved for11 fibromyalgia? I don't think that that's really 12 appropriate. So in learning this particular scenario and 13 building the field, we may have to think about excluding 14 these patients.15 How long should a trial be? It's actually 16 quite interesting. I've actually just come back from 17 Europe where I spent some time at the European League of 18 Associations of Rheumatology Annual Meeting, and I 19 actually walked around asking questions helter-skelter, 20 kind of like how long should a fibromyalgia trial be, and 21 I could get no consistent answers. Europe has a different22 opinion than the States. 1 200 2 1 In general, we would like to think of this 2 longer than shorter because this is a scenario, this is a 3 disease that's been around in the patient for a long time.4 We'd like to be able to see a substantial response that 5 actually is maintained for a period of time, to know that 6 something is an important modifier of that particular 7 scenario. So we're thinking about at least three months, 8 if not six months, and then guaranteeing at least a year 9 of exposure for safety and recognizing that most published10 trials to date have been much shorter.11 Should a patient have decreased symptoms and 12 for how long and without therapies? So one could even 13 imagine a scenario that if you have improvement over three14 months, can you think about low disease activity states a 15 la Dr. Wells or a cure by stopping therapy? Should we 16 require that a patient needs to have no therapy for a 17 period of time to be able to actually be improved with 18 this particular scenario?19 And then, the other question, of course, which20 comes up all the time is: what is the importance of the 21 tender points? Do we use it as a measure of outcome? 22 Should we use it as a criteria measure for inclusion, 1 201 2 1 based on how much disease activity they have, and thus do 2 we create a disease activity score as well as an outcome 3 score?4 And a la Dr. Clauw, is the FIQ an adequate 5 measure of function or should, in fact, other outcome 6 measures be developed, or should we begin to look at 7 what's presently available, either in the FHAQ, the 8 Fibromyalgia HAQ, or in the SF-36 and begin to apply that?9 And then, fundamentally, the two questions 10 really are represented by is it improvement in the pain of11 fibromyalgia or improvement in the disease? We'd like to 12 think it's the latter and not just the pain of 13 fibromyalgia.14 And what would a cure require? I will not 15 hold you to that question, but in fact it might be 16 something you want to keep in the back of your mind.17 Then the other question would be: in the 18 context of doing and designing a clinical trial for 19 outcome, what would be allowed concomitantly? Would 20 physical therapy be allowed? Would structured exercise be21 allowed? Would cognitive and behavioral therapies be 22 allowed? You've already seen evidence that there's 1 202 2 1 actually very good utility of cognitive and behavioral 2 therapy. We would have to stratify thus in that kind of 3 scenario, seriously increasing the number of patients in a4 clinical trial.5 Would psychotherapy be allowed in the trial? 6 Would ongoing therapy be allowed for patients who are 7 already on therapy as they recruit? These issues then 8 really do change whether or not you can recruit. How 9 could you recruit people if you don't allow some of these 10 issues? That's particularly true for the final one which 11 is medical therapy for depression.12 So in coming to conclusion, I'd like to point 13 out that in fact what is the perfect drug and, a la Dr. 14 Witter, the perfect drug is totally safe and totally 15 effective. Unfortunately, none exist. Not one drug is 16 totally effective and not one drug is totally safe. The 17 problem with asking the question of what is safe, what is 18 the benefit-to-risk ratio? And even more importantly, who19 should decide?20 We unfortunately are living in a society that 21 sometimes doesn't like to grapple with the important 22 questions related to being diseased and in fact also 1 203 2 1 doesn't really understand and recognize all the time what 2 it means to have a chronic scenario that alters your life.3 We have to make some decisions societally about what we 4 will accept as therapeutics, that we'll accept the costs 5 of those therapeutics, and part of the cost of those 6 therapeutics is not just money but safety. I don't have 7 any good answers to that.8 But I do believe I feel like this slide, which9 I've shown before in this scenario, like this individual 10 going to the diner and deciding, based on how much E.coli 11 might be infecting my hamburger, that in fact I have to 12 make the same kinds of decisions when I go to the counter 13 and make decisions about how I would apply drugs to myself14 or to my patients, and I have to weigh the benefit-to-risk15 ratio in each circumstance and kind of apply that in the 16 decision making process.17 It's critical for us in our decision making to18 allow our patients to understand that we actually do this 19 process on a regular basis and include them in that 20 decision making so that they can actually feel part of 21 that process in general.22 So I think that what we're actually asking 1 204 2 1 from you is to think about these issues. The questions 2 we're going to be showing you are actually long. They 3 have multiple components to them, but your input will be 4 critical for us to be able to make the next steps in 5 thinking about fibromyalgia as a model of chronic pain and6 thus is a model that we can use in that scenario and/or is7 it also a disease state where we can determine a way to 8 identify an outcome for the disease or syndrome of 9 fibromyalgia.10 So thank you very much.11 (Applause.)12 DR. FIRESTEIN: With that, we'll close the 13 morning session, and we will have a sumptuous lunch, I'm 14 sure. We will start again at 1:00. So that gives 15 everybody 42 minutes for lunch. We'll see you at 1:00.16 (Whereupon, at 12:18 p.m., the committee was 17 recessed, to reconvene at 1:00 p.m., this same day.)1819202122 1 205 2 1234567 AFTERNOON SESSION8 (1:05 p.m.)9 DR. FIRESTEIN: So why don't we go ahead and 10 get started?11 We have a list of seven questions that will 12 guide the discussion, and I think the easiest way to do 13 this is to just begin by reading the first question and 14 that will get us into the discussion. If you don't have 15 the questions, by the way, they're the back page of where 16 the agenda is. It should be in your stack of papers over 17 there.18 The first question is fibromyalgia involves a 19 constellation of symptoms. The ACR 1990 diagnostic 20 criterion is based solely on the number of tender points. 21 This definition may exclude patients who clearly have 22 widespread pain, non-restorative sleep, fatigue, et 1 206 2 1 cetera, but have 10 or fewer tender points.2 Should an alternative definition be developed 3 for fibromyalgia clinical trials with stratification by 4 number of tender points?5 So that's really two rather complicated 6 questions. Thank you, Dr. Simon.7 So perhaps somebody from the committee wants 8 to begin. Yes, Dr. Williams?9 DR. WILLIAMS: I'm not sure that they want to 10 start by trying to redefine it because those criteria were11 validated, and if you decide that you want to have a new 12 set of criteria, you're going to have to validate them 13 before you can use them. So even though it will eliminate14 some patients, we have the same problem with rheumatoid 15 arthritis and lupus, that there are patients who have the 16 disease who don't meet the criteria, but those who meet 17 the criteria, everyone accepts. So I would not change the18 criteria.19 DR. FIRESTEIN: Of course, one of the problems20 is that we now know, since the criteria were developed, 21 that those specific trigger points aren't necessarily 22 specific for fibromyalgia. As was pointed out, they 1 207 2 1 define diffuse pain.2 DR. WILLIAMS: They were not specific. 3 However, when they did validate the criteria, they looked 4 at a lot of different tender points and these were the 5 most discriminating but they're not specific.6 DR. FIRESTEIN: So is there general agreement 7 that we should or should not redefine the disease at this 8 point? Yes, Dr. Turk and Dr. Staud?9 DR. STAUD: The question is with overlap. I 10 think this is an important question. So when does someone11 become a patient with fibromyalgia and irritable bowel 12 syndrome and migraine headaches and so on?13 DR. FIRESTEIN: One of the questions is if we 14 define solely by pain, then we have this overlap of the 15 non-patient fibromyalgia patients or group of individuals 16 versus the patients which were described earlier, that 17 there are those individuals that have tender points and 18 have pain who don't seek medical help and that would be 19 included in a clinical trial and might be a potentially 20 different population of patients.21 Dr. Turk, did you have a comment?22 DR. TURK: Just a comment. About eight months 1 208 2 1 ago, there was an NIH meeting in which they brought 2 together all the people who had NIH grants on fibromyalgia3 and part of this meeting was to identify what should be 4 the directions for the future and for research, and the 5 number one thing that came up at this meeting was we 6 needed to have a new way of diagnosing or classifying 7 people with fibromyalgia, that it's really not a very 8 acceptable way that we're using right now. So it doesn't 9 answer your question as far as right now what we should 10 do. Larry, I think you were there. There were maybe 10 11 or 15 people at this meeting, all of whom agreed that the 12 classification system is really inadequate.13 DR. BRADLEY: Well, I guess maybe I'm not one 14 of the 10 or 15. And granted, I think there's sort of a 15 problem with error variance when you make a decision about16 is 10 tender points and not 11 tender points error 17 variance or is that something that's highly meaningful? 18 But I think if we radically alter the definition, then 19 essentially anything else that we produce in the future 20 will be based on different criteria. It'll be an 21 empirical question as to whether or not we're really 22 talking about the same phenomenon. 1 209 2 1 I think what's really interesting is that 2 there's a paper that came out in Pain several months ago, 3 and I've forgotten, I believe the first author's last name4 was Corli, I believe. But in this paper, they compared 5 responses to about five different pain sensitivity tasks 6 in groups of patients ranging from patients with 7 myofascial pain, regional myofascial pain, to 8 fibromyalgia. There were about five groups of patients 9 all in all. The most important finding was that the 10 people who met the current criteria for fibromyalgia were 11 sensitive to all five sets of sensitivity tasks using 12 different stimuli.13 So I think there is something about the use of14 the 18 trigger points that really distinguishes the 15 phenomenon that we call fibromyalgia from other types of 16 disorders that are characterized by chronic pain and 17 feeling badly and so on. So I'm a little bit reluctant to18 advocate that we radically revise the criteria at this 19 point.20 DR. FIRESTEIN: Jack?21 DR. CUSH: I, too, would argue strongly in 22 favor of using the ACR criteria because it's the one thing 1 210 2 1 that we do have that's rock solid, well tested, and it 2 should be the primary and only indication to get into the 3 study as fibromyalgia, whether you want other provisos on 4 top, that's okay, but these criteria have nothing to do 5 with what we're going to discuss henceforth, for which we 6 have less rigorous guidelines and validations. So that's 7 what I think is going to be the hard part of this 8 discussion.9 DR. FIRESTEIN: But maybe there should be two 10 goals. One is in the short term use the current 11 definition and in the long term try to develop a broader 12 definition, in part because most of the things that we're 13 planning on measuring as outcomes go beyond just simply 14 counting trigger points or tender points.15 DR. WILLIAMS: However, if you look at the 16 frequency of tender points, that exceeds the frequency of 17 inflammatory bowel disease or even chronic headaches. So 18 if you start adding too many things, you're also going to 19 start limiting your population.20 DR. FIRESTEIN: Dr. Simon?21 DR. SIMON: May I ask a modifying question? 22 If tender points then are going to succeed and survive, do 1 211 2 1 we then convert it into a dolorimetric measure which is 2 quantifiable rather than a finger measure which is 3 dependent upon who does it and how it's done? If we 4 believe that this is an important measure, should we be 5 developing a better quantifiable way of approaching it?6 DR. STAUD: This is one point that has been 7 tried to be made in lots of different investigations and 8 it has been shown to be very, very difficult. First of 9 all, tender points are overlying very different tissues. 10 Most of them are tendon insertion points but some of them 11 are muscles. In most populations to identify pain 12 threshold is a very difficult task. So most of these 13 tests have failed. So the number of tender points seems 14 to be the most solid measure.15 DR. FIRESTEIN: But isn't that how the 16 criteria that were developed, though?17 DR. WILLIAMS: I think dolorimetry came in 18 later. I think they just did the tender points initially.19 DR. FIRESTEIN: But how many people have had 20 the experience of going in to see a patient that the 21 resident has seen and has said that there are no tender 22 points, and then when we find the magic spots or push with 1 212 2 1 a little bit more vigor, then it becomes quite obvious? 2 So it's clearly operator-dependent. Is there not a better3 way of standardizing this?4 I guess we'll start over here. Yes, Dr. Turk?5 DR. TURK: There have been several attempts to6 develop procedures either dolorimetry or by patient 7 reports, and there are a couple standardized approaches 8 that have actually been published with standardized 9 training tapes of how to actually perform the exam. It's 10 called the Manual Tender Point Survey. I think Okifuji, 11 Terry Starz, David Sinclair, and myself were involved in 12 publishing some of those, and we showed they can be very 13 reliable by both physical therapists as well as physicians14 performing a standardized protocol.15 We also in that trial had patients not only 16 say yes or no, it hurt, but to rate how severe the pain 17 was and showed that the distribution of scores were much 18 better if you use a quantitative score than an absolute 19 number which was basically a normal distribution. If you 20 use the absolute number of tender points, it was a very 21 skewed distribution. So I think there is merit to 22 consider whether there are some ways, whether it's 1 213 2 1 dolorimetry or whether it's by patient ratings, that we 2 can get much more sensitive measure than just the absolute3 number of tender points.4 DR. FIRESTEIN: Dr. Katz and then Dr. Cush.5 DR. KATZ: I think the other issue, though, is6 whether that might be more appropriate for phase II rather7 than phase III studies. My own experience of trying to 8 standardize dolorimetry in a multicenter study is that 9 it's very difficult, very time-consuming. You can never 10 train enough and there are always reliability problems.11 However, if the distributions are better, 12 there might be some use in phase II proof of concept 13 trials, if there's an increase in sensitivity or 14 responsiveness to be gained from all that additional 15 effort, but in phase III, I would think that again you'd 16 probably want something more generalizable to the doctor 17 out there anyway who won't be doing dolorimetry. So I 18 would be opposed myself to requiring it in those studies.19 DR. FIRESTEIN: Could you just clarify? Do 20 you mean for entry criteria or for following response to 21 therapy or both?22 DR. KATZ: Either one. 1 214 2 1 DR. FIRESTEIN: Jack?2 DR. CUSH: I agree in that this has to be a 3 tool which has parallels with real-life practice and 4 dolorimetry would never be done in real-life practice, and5 Gary, when you say that we went in and found these trigger6 points, it really isn't because we pressed harder, it's 7 because we knew where to go more often than not. It 8 wasn't because we jumped on the patient, exerted 12 pounds9 per square inch, and I think it was just a simple blanch 10 of the finger pad. I think that it has to be a clinical 11 skill.12 If this is clinical skill, and it's to be part13 of the biometrics of clinical trials, then the clinical 14 trial design has to account for that in some way with 15 appropriate training and instruction at the outset of 16 those who will be the assessors, and this is what we've 17 done for RA trials. Especially in situations where the 18 person doing the assessments may not be the investigator 19 and may not be a rheumatologist, trying to standardize 20 your assessors in some way through training, I think, is 21 the best way to get around this without having to be too 22 mechanistic about it. 1 215 2 1 DR. FIRESTEIN: Although we heard earlier that2 the location of the pain was not necessarily specific. So3 that, that would belie what you had just commented on.4 DR. CUSH: But getting back to Jim's point, it5 is discriminatory, and it is part of the criteria. So 6 that's why we're talking about these tender points as 7 opposed to pain here, there, wherever. We know they hurt 8 all over. We're only going to count these 18 spots.9 DR. STAUD: One very important point, in order10 to decide if you want to do tender point counts or tender 11 point scores, is the tender points per se or tender point 12 scores do not really add anything to the overall 13 examination of these patients because they mostly highly 14 correlate with distress and not with measures that we're 15 actually trying to look at, like for example pain. So 16 that's why in most trials, people have gone away from 17 tender point scores. They just do tender point counts.18 DR. FIRESTEIN: Do you mean gone away from 19 tender points as an outcome or again as an entry criteria?20 Because most people do require it for entry criteria but 21 you don't necessarily need to count changes in number of 22 tender points as an outcome. 1 216 2 1 DR. STAUD: Actually, I was referring to using2 the tender point scores.3 DR. BRADLEY: Just to beat the horse one more 4 time, the dolorimeter is also operator-specific, and in 5 our lab at least, it takes anywhere from three to six 6 months to train a very bright graduate student to use the 7 dolorimeter reliably with our master doloritress. So it's8 very difficult to use it for outcomes.9 DR. KATZ: I'd like to raise a related point. 10 We've been talking about which criteria to use for entry 11 into the trial and we've been talking about the ACR 12 criteria, but a separate issue is whether we should 13 recommend that investigators further characterize their 14 population in some way so we can understand exactly what 15 type of fibromyalgia population they've studied. We've 16 heard already today that different populations with 17 fibromyalgia can really be on very wide range of disease 18 burden.19 Should we require that we characterize the 20 population in terms of what proportion have irritable 21 bowel syndrome, have migraine, have some of these other 22 features? Because that might make different trials 1 217 2 1 comparable or not comparable. Should we require that 2 there be some assessment of their severity of depression 3 or mood disturbance at baseline, so that we can know 4 whether we're comparing apples with apples when we look at5 different studies?6 DR. FIRESTEIN: Jack?7 DR. CUSH: To answer Nate's point, I would 8 suggest that along with this entry, belief in this entry 9 criteria, I think we should make strong statements about 10 exclusions to try to again unify the population. I think 11 that I wouldn't discount symptoms that may go along with 12 the disease, but I would try to eliminate confounders of 13 the disease. So whether that be uncontrolled psychiatric 14 illness, for instance, patients who have over-reliance on 15 narcotics. There are many issues that we may want to 16 exclude at entry to try to unify the population, and I 17 think that that's important and maybe even drugs might be 18 a key exclusion to being in the study.19 DR. FIRESTEIN: Lee?20 DR. SIMON: Well, it's all very interesting 21 that you've now pointed these out, both Nate and Jack. So22 of those things that you would leave in, would you 1 218 2 1 stratify for them, recognizing what that would mean from a2 numbers point of view and the implications of that? 3 Obviously, to allow you to have a larger population, not a4 smaller population.5 DR. KATZ: My own thought would be not to 6 stratify. My own view of stratification is when you have 7 robust knowledge that something is a clear-cut prognostic 8 variable and you have some sense for in what way it might 9 be prognostic, then it makes sense, but with these things,10 I think we have a general sense that people that are 11 sicker will probably not do as well, but right now, it's 12 just observational, I think.13 DR. FIRESTEIN: Dr. Williams?14 DR. WILLIAMS: I would agree. I think that if15 you start stratifying for these other various variables, 16 that you're going to have unmanageable numbers required. 17 At least in my population, pain is the most prominent 18 feature, and if you're going to evaluate for pain, that's 19 a whole different set of variables than if you're 20 evaluating for irritable bowel.21 MS. MATALLANA: Also, we hear from the 22 patients quite often that they're upset that they are not 1 219 2 1 able to participate in clinical trials because they're on 2 certain medications and things, and because of that, 3 there's the fear that there are groups of people that 4 maybe have more severe symptoms that are not being 5 included in the clinical trials.6 DR. CUSH: You might want to stratify for 7 medicines, so people who are on tricyclics or SSRIs, that 8 may be important because they may have some pain 9 modifiers, but I think you have to decide whether you're 10 going to allow pain modifiers. Should people who are on 11 background amitriptyline or terazadone be allowed in a 12 trial? That's an important factor, and I think that other13 clinical symptoms which are basically manifestations of 14 disease and more severe disease will have more of those 15 IBD or numbness or headache or back pain or TMJ, whatnot 16 are not as important.17 DR. FIRESTEIN: That question in terms of 18 concomitant medicines is going to come up with one of the 19 later questions. We'll probably discuss that because 20 that's one of the major issues in terms of designing these21 studies.22 But in terms of stratifying for number of 1 220 2 1 tender points, I think, is there general agreement that 2 that's not going to be particularly useful?3 DR. WILLIAMS: I understood Lee's question not4 only stratifying by number of tender points but 5 stratifying by other associated conditions.6 DR. FIRESTEIN: Right, although the actual 7 question as originally stated was by tender points, and 8 then the second question is whether or not one looks at 9 different subpopulations as just pain or pain with 10 concomitant syndromes, like cognitive impairment, et 11 cetera.12 Lee, did you have another comment or question?13 DR. SIMON: No.14 DR. FIRESTEIN: So.15 DR. HOFFMAN: A question, Gary?16 DR. FIRESTEIN: Yes.17 DR. HOFFMAN: Not being someone who has 18 studied fibromyalgia in a pharma way, a question for some 19 of the panelists who have would be related to the 20 specificity of the current ACR criteria.21 What hasn't come up today is the patient who 22 perhaps comes in with a dozen trigger points but perhaps 1 221 2 1 not any of the specified 18 and these are non-articular 2 and do not follow a pattern of peripheral inflammatory 3 disease. What kind of specificity is lost if such people 4 are included, if they have other characteristics that 5 we've listed here, non-restorative sleep, fatigue, 6 headaches? Are we losing from some of these studies a 7 significant number of people who should be included?8 DR. FIRESTEIN: Are there any comments?9 DR. STAUD: Yes. I think really one of the 10 hallmarks of fibromyalgia is widespread pain and 11 widespread tenderness. So I think the distribution and 12 number of tender points or the number of tender points 13 really expresses the widespread distributions is extremely14 important. So we couldn't really cut back and say we 15 don't care where tender points are measured or tender 16 areas. It has to be in a widespread distribution as 17 originally defined by the ACR criteria. It should be.18 DR. CUSH: But I think adhering to the ACR 19 criteria which are not dependent upon fatigue and 20 cognitive impairment but instead are dependent upon 21 widespread pain and its definition, if you meet that, then22 I think the stringency is not that different than what we 1 222 2 1 have for RA, that you are going to get patients with more 2 severe disease, but then again there may be patients with 3 enough severity or enough pain that it's also modifiable 4 by some intervention.5 So while we're going to miss a lot of people 6 in the real world -- they're poorly characterized but 7 nonetheless are going to get treated in the real world -- 8 I still think that sticking to more rigid criteria allow 9 you to work with the data in a way that's going to either 10 show the benefit or non-benefit of an intervention.11 DR. FIRESTEIN: Well, the group has spoken.12 DR. WITTER: Could I just ask maybe for a 13 little bit more discussion, and it might be useful then 14 for the other questions? If we are to evolve in terms of 15 an approved outcome or inclusion criteria or definition 16 for fibromyalgia, suggestions on how that would be done in17 trials that come to us? This might be a safe place to 18 begin that discussion.19 DR. CUSH: Could you rephrase that?20 DR. WITTER: Well, it's nice to say that while21 we should come up and develop this, that, or the other 22 thing, but I think in this area in particular, as we're 1 223 2 1 moving forward, we don't have the luxury of the 2 experiences that we had in RA or OA and that we may have 3 to do more or less kind of real-time validation of new 4 whatever it is.5 Could you begin to discuss that maybe now? Is6 this the place? Would you like to entertain that? On how7 we on this side of the fence could encourage that kind of 8 a process and not compromise what it is that we see?9 DR. FIRESTEIN: Jack?10 DR. CUSH: I think you have to go with our 11 primary outcome variable, and with RA and other diseases, 12 we have composite measures, and I think that this is a 13 syndrome that has many facets to it, to stick to only pain14 as a single outcome variable by whatever measure would be 15 a major mistake. I think that we should invoke pain as a 16 primary outcome that must be achieved but others as well, 17 and so whether that is sleep, function, fatigue, I 18 wouldn't go much beyond that. I wouldn't want to start 19 listing headache and numbness and TMJ and IBS and all the 20 other things that go along with it, but I would try to 21 choose those features of the disease which are major -- 22 they may be inter-related amongst each other. Pain and 1 224 2 1 fatigue go together. Sleep and pain go together. 2 Nonetheless, I think that they may also have their 3 independent contributors to the disease.4 So an intervention or set of interventions 5 that could improve more than one domain is what I think we6 should be going after.7 DR. FIRESTEIN: Dr. Katz?8 DR. KATZ: Just a clarification, Jim. I heard9 you ask about developing improved diagnostic criteria, but10 I think Jack's point was addressing mainly developing 11 outcome measures. So in terms of your question about 12 entry criteria, I think we have to ask ourselves whether 13 it's appropriate for us to require that sponsors of 14 studies develop new diagnostic criteria for fibromyalgia.15 As Dennis has already said, there are already 16 efforts going on in that regard or that hopefully will go 17 on at the NIH level, and obviously whatever we develop has18 to be responsive to improve diagnostic criteria that 19 develop. But as far as entry criteria go, I think we need20 to decide whether it's our role to require somebody to 21 develop a new entry criteria.22 Outcome measures, I totally agree with what 1 225 2 1 Jack is saying. I think it would be more appropriate 2 there to encourage sponsors of research to develop 3 appropriate outcome measures for the medications that 4 they're trying to get approved, but for entry criteria, I 5 don't feel the same way.6 DR. FIRESTEIN: But was your question 7 primarily at entry criteria or outcomes?8 DR. WITTER: It's really a general how-to 9 question. Outcome variables, anything to move this 10 disease in particular forward. It's really a question of,11 in terms of from our end, how do we do it? What are the 12 ways that would not come up with undue burdens to the 13 sponsors, would not be compromising what's going on in the14 research community in general. I think we're searching 15 for ways that we can be helpful in the process but not be 16 burdensome, and so I think it's a how-to question more 17 than anything.18 DR. FIRESTEIN: You're precisely right that 19 it's going to end up being real time, and although we have20 acceptance of the ACR criteria, for instance, for RA, it 21 is still being re-evaluated constantly real time, and 22 there's some discussion as to whether or not measuring 1 226 2 1 tender and swollen joints adds anything to some of the 2 other outcome measures.3 So I think what in the end is going to happen 4 is we take our best guess at what makes the most sense, 5 and those would include a few different domains that have 6 been discussed, including pain, patient global 7 assessments, and perhaps some measure of patient function,8 and then use that to go forward and then have to, again, 9 validate it real time.10 Jim?11 DR. BRADLEY: I think with regard to the 12 question of function, I think expecting that a trial of a 13 pharmacologic compound to change function over a very 14 short period of time would be very unrealistic, and I 15 think it would be overly restrictive in terms of measuring16 outcome. I think one has to remember that apart from the 17 measurement problems of function that were described this 18 morning, function in the patients who come for treatment 19 and patients who would enter these trials, functional 20 disability is in part determined by long periods of 21 sitting and inactivity and it's a whole conglomeration of 22 factors that influence current physical function. 1 227 2 1 So I think to expect any compound to change 2 function in a short period of time would be really 3 unrealistic, and I think it'd really be much more 4 appropriate to focus on alterations in pain and 5 alterations in global assessment.6 DR. FIRESTEIN: Lee?7 DR. SIMON: So we've actually moved on to 8 question 2.9 DR. FIRESTEIN: I was going to say. We're 10 well into question 2 right now, which relates to would it 11 be reasonable to expect that a product that is truly as 12 efficacious, but I assume you mean effective, --13 DR. SIMON: Yes, but we don't use the term 14 effective in this world.15 DR. FIRESTEIN: I understand. For the 16 treatment of the syndrome would show improvement in pain, 17 some measures of physical function, and the patient global18 assessment, and then what would be the optimum duration? 19 Because as you pointed out, a short duration trial might 20 improve patient global assessment but might not have an 21 impact on patient function.22 DR. SIMON: And I'd like to address that 1 228 2 1 particular issue since in fact we had a recent meeting in 2 the rheumatoid arthritis arena to discuss the issue of 3 physical function, and we presented evidence that within 4 16 weeks -- so thus 4 months and remember we're talking 5 maybe a 6-month trial here -- that in the context of a 6 chronic disease with structural implications, you can 7 actually against placebo measure differences in 8 improvement in physical function. For those of you on the9 committee who will remember that discussion just two-three10 months ago.11 That's actually a very important point. In OA12 and RA, there's a high correlation between pain and 13 function. The functional outcomes are robust and well 14 developed. Those measures are robust and well developed. 15 The FIQ, you've already heard about here, has not been a 16 terrific instrument, based on the particular activities 17 that people are doing today and thus might need to be 18 addressed. Nonetheless, we know at least using the FIQ 19 that there isn't a great correlation between pain and 20 function.21 I find that a little weird. I think that in 22 almost all other circumstances, there's a tremendous 1 229 2 1 correlation between pain and function. So I don't 2 understand if it's unique to fibromyalgia that there's not3 or it's just that it's a lousy functional measure and 4 that's why there's no good correlation. So we at the 5 agency are uncomfortable in thinking about an improvement 6 in a scenario such as fibromyalgia that does not include 7 some measure of function as pain improves.8 We have actually had an example of a therapy, 9 based on trial design which was statistically significant 10 improvement in pain of several millimeters in measurement,11 but in fact in the concept of function failed miserably in12 a traditional realm where function and pain are linked. 13 So we are very uncomfortable in not looking at this as a 14 gestalt rather than just the pain of.15 Might we entertain a little discussion here 16 about whether or not there is any linkage between pain and17 function, and if there is, should there be a requirement 18 that we begin to work on a different kind of functional 19 assessment that might be better or unique and give us a 20 better correlation? Not because we're just trying to 21 create the better correlation, because we're trying to 22 measure the overall state of the patient. 1 230 2 1 DR. FIRESTEIN: Dr. Cush?2 DR. CUSH: Lee, would you accept a quality of 3 life measure as a functional measure as well? So like SF-4 36 in whole and then take out the physical component in 5 part. What's your comment on that?6 DR. SIMON: I think that I have been educated 7 by any number of brilliant people to be convinced that 8 health-related quality of life measures are similar to 9 function but not always the same. SF-36 as a generic is 10 not necessarily not applicable to specific diseases, and 11 HAQ, which is supposedly non-generic, might be generic, 12 depending on the circumstances. So I think that this is 13 an evolving field.14 I think I've learned to think of the SF-36 as 15 a very good measure, a very robust measure. You have to 16 be specific about which components of it you can use. It 17 has not been validated in all these diseases, but every 18 time I look at it being applied to various different 19 syndromes and diseases, when done correctly, it looks like20 it discriminates and is valid.21 So under those circumstances, I would not 22 distinguish, and I think that if a generic measure, such 1 231 2 1 as the SF-36, is proven to be useful and have utility, I 2 think that would be great.3 DR. FIRESTEIN: One doesn't necessarily need 4 to have an improvement in function in order to have a drug5 approved for rheumatoid arthritis.6 DR. SIMON: No, and that's a very interesting 7 point. From an educational point of view, we approve 8 drugs for a separate indication, meaning there's the 9 indication of signs and symptoms, there's the indication 10 for x-ray progression, meaning inhibition of x-ray 11 progression, and a separate indication that the sponsor 12 has to go for for the improvement of physical function, 13 and that's exactly right.14 We could create the same scenario here and not15 just apply that in the context of improvement of outcome. 16 However, the caveat to that is the HAQ is now being 17 considered as very important for even getting signs and 18 symptoms, and we're actually evolving to consider that all19 studies in rheumatoid arthritis would have to include some20 physical function outcome, even though it may not be 21 measured or expressed in the HAQ.22 DR. FIRESTEIN: Does anybody have any comment 1 232 2 1 on whether or not there should be a separate physical 2 function component that's required for fibromyalgia? Yes?3 DR. TURK: To answer part of your question, 4 Lee, in back pain area as an example, there are lots of 5 data to show that the correlation between function and 6 pain is about .3 and there are studies in neuropathic pain7 to show that the relationship between pain and function is8 fairly low. So I don't think it's unique to fibromyalgia 9 that there isn't a high correlation between pain and 10 function. What that says to me is that function is an 11 important outcome that should be considered, in addition 12 to looking at pain.13 Unlike Dan Clauw who's left, his last 14 statement that if there was a treatment that was effective15 in reducing pain but had no beneficial effect on function,16 he would view that that's positive. My response would be 17 to have someone who's a 45-year-old person with a 7-year 18 history of fibromyalgia who had a statistically 19 significant improvement on pain but then said but I'm not 20 doing anything any differently and not functioning any 21 better, to me, that's not a great outcome.22 Now, we could debate and I'm sure you might 1 233 2 1 argue with me about that, but at least it does speak to my2 concern that I agree with you. I think that we should 3 come up with some measure of function, whether it's the 4 FIQ, we could again talk about that, but I don't think 5 that we should take pain -- I disagree with Larry. I do 6 think you could take functional changes because it depends7 on how you're defining function, Larry. If you're talking8 about lifting huge amounts or walking great distances, you9 might not expect to see that in a couple weeks, but if 10 you're talking about improvement of sleep and improvement 11 in ability to do things around the home, in fact, you 12 might see those kinds of changes. So it really depends on13 how you're thinking of function.14 DR. BRADLEY: Yes, I agree with you on that 15 point, Dennis.16 DR. FIRESTEIN: Lynne, Jack, and then Jim.17 MS. MATALLANA: From the patient's viewpoint, 18 our survey showed that even 20 percent improvement in pain19 would be a worthwhile outcome. I agree, that I don't 20 think pain has as much of an effect on functionality. I 21 think the fatigue issue does. But at this point, we don't22 have many options for fatigue improvement. So if we can 1 234 2 1 eliminate the human suffering of pain, I think that the 2 benefits would be tremendous to the patient population.3 DR. CUSH: I think that we have to sort of 4 move forward. In the past, with all of the diseases we 5 consider, we have always done short-term trials, single 6 variable outcomes, mainly looking to improve a single 7 symptom or a group of symptoms, and I think the trend has 8 been at the FDA and as mandated or required by clinicians 9 and researchers that we should go towards longer-term 10 trials with multivariate outcomes which are more true to 11 life that actually don't speak to symptom improvement, 12 really to true disease improvement, and that that has 13 long-term implications that impact on a patient's life and14 employability and whatnot.15 I think that we should go toward a functional 16 indication. I think that since we don't know which is the17 best, I think that the FDA should accept a group as being 18 reasonable measures, whether it's the four being the FHAQ,19 SF-36, FIQ, or even WOMAC, and require a sponsor to do out20 of those four. And if you improve in one, that's good 21 enough. Overall, it shouldn't be function and pain 22 because, as has been said here before, there are people 1 235 2 1 that may not improve their function, even in a 6-month 2 trial.3 So again, going towards a multivariate 4 definition, we should require function as one of several 5 measures that we may accept. Pain is first and we may 6 accept some others as being part of some overall 7 definition that we're going to call a response in 8 fibromyalgia.9 DR. WILLIAMS: I don't have a lot more to add,10 except I agree with both of them.11 I have a question on what Jack said. I would 12 not require long term on the initial studies. I would 13 require 3 to 6 months with longer-term follow-up to see 14 how long the response lasted, but I wouldn't require them 15 to show benefit over a 1- or 2-year study like we do in RA16 now. And I agree that I think physical function is an 17 important variable.18 MS. McBRAIR: I also agree that physical 19 function is important. You're talking about younger 20 people. They have a long life ahead of them, and we need 21 to see them make some progress in that area. However, as 22 long as it's part of a number of variables like Dr. Cush 1 236 2 1 mentioned, I think I could be comfortable with that.2 DR. FIRESTEIN: Nobody is disputing that 3 physical function is important. The question is: is that4 going to be a primary outcome? If you improve symptoms, 5 for instance, is that good enough to get a drug approved? 6 The gold standard would be that not only would symptoms 7 improve but also people would have improved function, go 8 back to work or whatever, but is that going to be the 9 standard to which anything that gets approved for myalgia 10 be held?11 Jim?12 DR. WILLIAMS: I think pain has to be the 13 primary outcome measure. That's what the patients are 14 complaining of, but I think an important other measure 15 would be physical function and patient global assessment 16 which would include the fatigue and everything else.17 DR. KATZ: I'd like to emphasize and maybe 18 elaborate a little bit more on that proposal with an 19 analogy.20 If you think of something like pneumonia where21 somebody has chest pain, cough, fever, sputum production, 22 whatever, if you give them morphine, it's going to help 1 237 2 1 with their chest pain. It's going to reduce that symptom.2 It's going to reduce their cough, but you wouldn't call it3 a treatment for pneumonia. Yet, thank God, it's there and4 we should be applying it to people with pneumonia or 5 something like it, codeine, dextromethorphan, what have 6 you.7 Likewise, if there's a treatment that improves8 the pain of fibromyalgia, I think that we should have some9 mechanism by which that medication can be made available 10 to the patients who just told us that they'd be happy to 11 see something like that come down the pike. So my own 12 thought is that we should have a label that says improves 13 the pain of fibromyalgia, and I don't know, maybe we 14 should even extend that to the fatigue of fibromyalgia or 15 other things. I guess it could get complicated.16 But then, in addition to that, recognize that 17 there are treatments for pneumonia and if something does 18 reduce the whole symptom complex of fibromyalgia, it 19 reduces the patient's pain and fatigue, cognitive 20 dysfunction, whatever, and we feel that by some 21 biologically plausible mechanism, it's actually addressing22 the underlying disease, well, that should be further 1 238 2 1 recognized by a label that says this is a treatment for 2 fibromyalgia and, obviously, it will reduce the symptoms 3 that go along with that disorder.4 DR. FIRESTEIN: Dr. Anderson, and then Dr. 5 Lasky.6 DR. ANDERSON: I just wanted to say that 7 although pain is of primary importance, the question 8 before us is whether if a product is supposed to be truly 9 efficacious for the treatment of the syndrome, you should 10 expect it to show improvement in pain, physical function 11 and patient global, and I would answer yes to that.12 DR. LASKY: My concern would be the definition13 of functionality because I've heard agreement around the 14 table that certainly improvement in functionality is a 15 positive outcome. There's no question about that. But 16 without clear definitions of what would constitute 17 functionality, I think the manufacturer would be at a 18 specific disadvantage.19 In addition, in terms of the length of the 20 study, it's possible that pain relief may occur first and 21 functionality later, and by continuously monitoring 22 patients, the trials can continue after the drug has 1 239 2 1 already come to market. But in order to make that claim 2 for an indication, there has to be a line in the sand 3 defining, in fact, what functionalities would be 4 approvable by the FDA.5 DR. FIRESTEIN: So, Lee, would the agency 6 consider dividing things up as has been commented upon, 7 where you have the pain and fatigue of fibromyalgia versus8 fibromyalgia as a global indication?9 DR. SIMON: Well, I think that we'll consider 10 anything that the committee suggests. That's why we're 11 here. We have no preconceived notions. That's the other 12 reason why we're here. A responder index might be exactly13 the way to go about doing this in the context of each of 14 those areas, the pain of, the fatigue of, the blah-blah-15 blah of, and we are partial to that in a multidimensional,16 multisystemic disorder, such as this one. It has a lot of17 logic to it.18 What doesn't have a lot of logic is to have to19 create a bar where you have to win on multiple things that20 there's a lot of argument about.21 DR. FIRESTEIN: I think most people would 22 agree with that. 1 240 2 1 Yes, Jim?2 DR. WITTER: Can I just have a bit of a 3 discussion then on the pain metric itself in terms of, I 4 had mentioned earlier, we're always concerned about 5 overpowering of studies, that you can get a statistically 6 important result, but it has no clinical meaning. John 7 Farrar has come out recently with something suggesting 8 that a 33 percent effect size is what you should shoot for9 in a chronic pain condition.10 Could I have some discussion on if it's the 11 pain component, what should that look like?12 DR. FIRESTEIN: Sure. Who would like to 13 comment on the pain component? Dr. Katz?14 DR. KATZ: Dennis and I are having a secret 15 visual communication.16 (Laughter.) 17 DR. KATZ: We just finished having this 18 IMMPACT meeting that has been alluded to several times, 19 and I think Jim, you were there, and just to reiterate for20 the rest of the group, that's a group of people who spent 21 a lot of time reviewing all of the pain measures that have22 been used for chronic pain clinical trials. Basically the 1 241 2 1 long and the short of it is that after that extensive 2 review, that group came up with a recommendation of if 3 we're looking for a unidimensional pain intensity measure,4 then a 10-point numerical rating scale was, for a variety 5 of reasons, the recommendation.6 DR. CUSH: How much improvement required?7 DR. KATZ: The issue of what's a clinically 8 significant improvement is a completely different question9 and to comment on that, it seems to me that the proportion10 of reduction of pain intensity that's clinically 11 significant depends somewhat on the scenario. John Farrar12 has work related to neuropathic pain and also to cancer 13 pain, just those two entities, but we don't have any 14 evidence that those results necessarily extend to other 15 areas.16 My understanding of that same issue in the 17 acute pain literature where people have tried to compare --18 say, for example, with the stop watch techniques where you19 see when the patient clicks the watch is meaningful versus20 what the pain intensity difference is, my understanding is21 that it's closer to a 50-percent reduction in acute pain.22 And in our own study on chronic low back pain, 1 242 2 1 looking at a non-steroidal anti-inflammatory drug -- we 2 haven't published this yet but we're working on it, and it3 looks also like it's more like about 50 percent relief. 4 It correlates with the patient global improvement of 5 meaningful.6 So I think that if people wanted to find what 7 the clinically significant differences are in 8 fibromyalgia, it will have to be defined in the context of9 the specific field.10 DR. STAUD: I was wondering if you could 11 elaborate on this somewhat more, because I think most of 12 us are aware of the problems with 10-point scales 13 regarding linearity and comparison. So you could easily 14 have someone who improved from a 9 to an 8, and the 15 difference from 9 to 8 may be much less than a difference 16 from a 4 to a 5. So I think for this reason, VAS scales 17 have shown in multiple validation trials to have linearity18 and seem to be a better measure of change compared to 10-19 point scales.20 DR. KATZ: Dennis, I don't know if you want to21 comment on that. My understanding is that there are some 22 studies that suggest that the VAS is a ratio scale whereas 1 243 2 1 the numerical scale doesn't have quite those ratio 2 properties, but that in practice they both do exactly the 3 same thing. Dennis, I don't know if you want to elaborate4 on that.5 DR. TURK: I'm not sure I want to elaborate, 6 but the IMMPACT process did commission a background paper 7 that addressed that particular issue, and in addition to 8 raising the point that Nat just made about the linearity, 9 and it looks like it's basically the same, whether you 10 have a 10-point numerical scale or the visual analog scale.11 There are several studies showing, especially 12 with older populations, difficulty using visual analog 13 scales and not understanding how to use mid-points and 14 tend to use extremes. So the IMMPACT group recommended 15 against using visual analog scales, mainly because of the 16 difficulty with using it across populations of different 17 ages.18 DR. FIRESTEIN: Jim?19 DR. WITTER: Could I press Nat a bit to expand20 upon your earlier comment then? If fibromyalgia should be21 viewed differently from other chronic pain models, I'll 22 use that term, why should that be the case in terms of a 1 244 2 1 33 percent with, let's say, lower back pain? I mean, why 2 should this be different?3 DR. KATZ: Well, I think it's an empiric 4 question. If the question is what percent reduction in 5 pain intensity is best predictive of the patient global 6 response as being good to excellent or better or 7 meaningful on a stop watch of wherever you decide the 8 patient is going to report to you their own sense of 9 whether their response is meaningful, to me, it's an 10 empiric question as to whether that number is the same 11 across multiple different disease entities. I don't think12 there's any reason to think that God made it that way and 13 that it has to be the same across all different disease 14 entities.15 In terms of what data exists to address that 16 empiric question, the only data that I'm aware of is John 17 Farrar's work with the pregabalin in neuropathic pain and 18 the work he did with the Actiq lozenge where he showed 19 that if you use the metric of the patient's behavior of 20 taking a second rescue dose as a sign of meaningful 21 analgesia, a 33 percent reduction of the pain intensity 22 that they started with at the time of that breakthrough 1 245 2 1 episode was the degree of pain reduction that best 2 predicted that the patient would not need to take a second3 rescue dose. So two different ways of getting at the 4 clinical meaningfulness question. Both miraculously gave 5 about a 33 percent reduction as the answer which is 6 interesting that it's so consistent but still doesn't 7 prove that it's going to be the same in other disorders, 8 and we have these counter-examples.9 My understanding in the acute pain scenario is10 that in fact it's not 33 percent but it's more like 50 11 percent, and our preliminary work with chronic low back 12 pain and NSAIDs suggests that it's more like 50 percent.13 The other issue is that we don't have any 14 reason to believe that it's the same across drugs. The 15 amount of reduction in pain intensity that may be 16 associated with a patient rating of satisfaction may be 17 different with opioids and with NSAIDs. My own sense of 18 the literature, having looked at that informally, is that 19 probably patient satisfaction may be associated with a 20 lower pain intensity difference with the opioids which may21 independently modulate affective components of pain 22 compared to the NSAIDs. So there's no reason to think 1 246 2 1 that it's the same across all these different situations.2 In fibromyalgia, if there's literature that 3 directly assesses the degree of pain reduction that's best4 correlated with patient global assessments, I'm not aware 5 of it, but it would have to stand on its own for 6 fibromyalgia, I think.7 DR. FIRESTEIN: Dr. Gibofsky?8 DR. GIBOFSKY: I don't pretend to know what 9 metric should be used to measure pain and since I don't 10 know what metric should be used to measure pain, I don't 11 know what the MCID for that metric should be, but the one 12 thing I would argue strongly for -- and I'm influenced by 13 what Ms. Matallana had to say -- is that whatever metric 14 we recommend should be one that can be simply applied and 15 utilized by the non-specialists. Our patients are telling16 us that they want care from a non-specialist and most of 17 the trials will be done by the non-specialists.18 The incidence and prevalence data of 19 fibromyalgia suggest that it's just not possible for all 20 of our patients to be seen by any of the specialties 21 represented here today, and so we need metrics that go 22 beyond the sophistication of the specialists that can be 1 247 2 1 easily applied.2 The dichotomy between the devices that we 3 determine for clinical trials and the actual data that we 4 collect in clinical practice is often quite wide, and I 5 think it would be problematic if we devise metrics for 6 clinical trials that could not easily be adapted to 7 clinical practice, particularly by non-specialists.8 DR. FIRESTEIN: The number that came from your9 study was approximately a 20 percent improvement, and I 10 think that's a reasonable place to start when trying to 11 sort through. That is, what do patients find would be a 12 clinically meaningful improvement in terms of at least 13 pain? I mean, that number needs to be validated in some 14 way obviously, but at least it's a reasonable starting 15 place. You know, from an empiric perspective, amounts 16 like 50 percent sound to me to be too high of a bar in 17 terms of trying to achieve in a clinical trial.18 Jack?19 DR. CUSH: I agree with those comments, and 20 moreover, I think that the studies that I think Nat is 21 talking about are using pain as primary outcome variables,22 and here, pain would be part of a composite definition, 1 248 2 1 wherein such stringency is really not required. A lower 2 level or minimum threshold of 20 percent could be 3 reasonable if linked to a sequence of other "if" 4 statements that then lends further credence to that 5 initial 20 percent in pain improvement.6 DR. FIRESTEIN: Dr. Witter?7 DR. WITTER: Just two things on clarification.8 In acute pain, the discussion I think we should -- if we 9 wander into acute pain, we should do so carefully. 10 There's no argument, I think, from our end that in an 11 acute pain setting, pain and function are essentially the 12 same thing, and it's a very different setting, being post-13 op, I think you would agree, than having fibromyalgia. So14 I think we should wander into that carefully.15 I just wanted a clarification. The 20 percent16 that we're referring to for fibromyalgia, that is the 200 17 responses from the 16,000 actually sent out?18 MS. MATALLANA: We sent out 16,000. We had 19 1,119 responses, of which 200 we were able to tally, and 20 of that 200, 20 percent was the majority figure of needing21 to have improvement at that point.22 DR. WITTER: Thank you. 1 249 2 1 DR. FIRESTEIN: I mean, that's obviously a 2 very limited sample, but it does make some empiric sense 3 that that's the general range that people might find 4 useful in a treatment that had minimal side effects.5 Just to come to the second part of the 6 question in terms of the duration of clinical trials, most7 of the numbers that have been tossed about have been sort 8 of in the 3- to 6-month range. Is there a lot of 9 discussion on that? Of course, Dr. Cush.10 DR. CUSH: I think to go anything less than 6 11 months would be a mistake, but at the same time, I do 12 think that whatever guidelines we put forth, that they 13 should be ones that are, A, meaningful but also, B, tend 14 to promote investigation and drug development in this 15 area, and so to develop too many hoops to jump through for16 studies that are too long, then who cares if there's 10 17 million people with the disease. We're just not going to 18 go there. We'll go after simple pain indication and do it19 that way. So I think that again if 3 months actually 20 improves the likelihood of that, then fine, but I think 21 ideally 6 months should be the minimum.22 DR. FIRESTEIN: Yes, I would agree with that. 1 250 2 1 Jennifer?2 DR. ANDERSON: I'd just like to comment that I3 agree that 6 months is a good length, but for these sorts 4 of trials, that you presumably would have multiple 5 observations made during the trials, so you could 6 determine how long it took for the drug to begin to be 7 effective, so that the speed of action could also be 8 determined.9 DR. FIRESTEIN: Gary?10 DR. HOFFMAN: I agree with Jack that 6 months 11 seems like a reasonable minimal period of time, but the 12 question is what would be the optimal duration, and given 13 that this is a chronic disease and that the drugs that are14 going to be tested may be agents to which there is some 15 adaptation and loss of effect over time, I think it'd be 16 terribly important to know what the treatment response 17 curve was over a more chronic period of time. So I'd be 18 in favor in responding to the charge of what would be 19 optimal duration to be thinking more in terms of a year.20 DR. FIRESTEIN: Why don't we move on to the 21 next question then, which is not posed with equipoise. It22 says: does the committee agree that placebo-controlled 1 251 2 1 studies with analgesic rescue are a primary requirement in2 fibromyalgia?3 I think placebo-controlled studies are a 4 reasonable approach to this, Dr. Simon. Does anybody 5 disagree with that? Dr. Simon disagrees with his own 6 question.7 (Laughter.)8 DR. SIMON: If we are to accept the 9 possibility of true placebo-controlled trials, what does 10 that mean to everybody around this table? What would be 11 the background therapies that would be acceptable in that 12 there is really no standard of care? Standard of care is 13 very much up in the air and has a lot to do with 14 components of treating aspects of the disease. There are 15 many antidepressants, such as tricyclic antidepressants, 16 that, as Nat previously noted, treat fundamentals of 17 fibromyalgia, at the same time treating the depression.18 So I would presume the committee is not really19 thinking about a 6-month trial of absolute real placebo 20 compared to standard of care. So could someone comment 21 about those implications?22 DR. FIRESTEIN: That's not really the 1 252 2 1 question. You didn't ask if this would be an add-on or 2 not, but whether it's as an add-on or a single agent, I 3 think everybody agrees that it should have a placebo 4 control to it.5 Now, that actually brings us to the next 6 question, which is: what are the concomitant medicines 7 and in particular those related to depression?8 DR. WILLIAMS: Can I address question 3 first 9 with analgesic rescue? Because we've done OA trials with 10 analgesic rescue using 4 grams of acetaminophen and have 11 patients who tolerated that. Now, whether fibromyalgia 12 patients will do that or not, and to respond to the 13 question as written, I would say you could have a placebo-14 controlled trial with acetaminophen rescue.15 DR. SIMON: I'd just like to point out the 16 caveat to that. There's a very famous study with 17 hyaluronic acid with concomitant acetaminophen rescue 18 where there was no evident capacity of the study drug to 19 actually benefit the patient since they achieved 20 appropriate analgesia with the acetaminophen. So one 21 thinks of rescue in two different ways. Is analgesic 22 rescue with acetaminophen withdrawal and failure of the 1 253 2 1 study drug or is it concomitant therapy and background 2 where then you're measuring from where you start off with 3 with the analgesic background a la add-on trial, and then 4 how do you ascertain the benefit? Would you then expect 5 the same 20 percent improvement that you would with no 6 background therapy?7 So the first question is: would the analgesic8 rescue be failure of the study drug, thus withdrawal? And9 the second question is: if you're thinking about it as 10 concomitant background therapy, would you then design a 11 different kind of trial analysis defining a disease 12 activity score at the inception of the new study drug on 13 the context of the background therapy and following and 14 determining the outcome with the same disease activity 15 measure subsequently?16 DR. WILLIAMS: You make it a lot more 17 complicated now. I think that if acetaminophen is going 18 to complicate your response, then they don't need another 19 drug. But you can't ask them to go on placebo without any20 benefit of anything else. So that, in the OA studies, 21 using that as an example, we didn't expect acetaminophen 22 to give total control, but we gave them some analgesic 1 254 2 1 benefit if they needed it, and I think if that complicates2 the response to analgesia, then probably the drug doesn't 3 offer a lot of extra benefit.4 DR. FIRESTEIN: We'll now move on to the next 5 question, which is related to treatment of depression and 6 other concomitant medications.7 So who would like -- Dr. Cush?8 DR. CUSH: So the answer is no, patients with 9 depression on full dose regular daily meds for depression 10 should not be excluded. However, patients with 11 uncontrolled depression with a BDI, Beck Depression 12 Inventory, of a certain scale should be excluded as a 13 measure of being uncontrolled. I think that would be 14 reasonable.15 I think con meds should be allowed, SSRIs. I 16 think the real issue, I'd rather defer this to Nat and 17 others who may know because my impression is that the use 18 of tricyclics could clearly confound all this. Unless 19 that were to be stratified for in trial design, I would 20 not like/allow/want to have pain modifiers, such as 21 tricyclics, in the trial.22 DR. WILLIAMS: I would think if you're using 1 255 2 1 pain as a primary outcome measure, you'd also want to 2 excludes opiates.3 DR. FIRESTEIN: Well, would opiates be written4 in as your analgesic rescue since NSAIDs are of marginal 5 value?6 DR. WILLIAMS: Well, previously, I said I'd 7 use acetaminophen as analgesic rescue, and I wouldn't use 8 NSAIDs, but I think that if you're using pain as your 9 primary outcome measure, once you start using narcotics, 10 you really complicate things because they may give you 11 benefit with adding complications further down the road.12 DR. FIRESTEIN: What about studies with either13 tricyclics or SSRIs or various combination drugs? How 14 does one manage a clinical trial if they're being treated 15 with an SSRI, for instance, or tricyclic for depression?16 DR. WILLIAMS: I actually agree with Jack, 17 that I think you do eliminate tricyclics, and I think if 18 they have depression that is controlled and you have to 19 figure out how long you want it to be controlled. We do 20 this with steroids in RA trials. They can be on steroids,21 if they've been on them for a period of time and they 22 don't change. You could say that if they have depression 1 256 2 1 and they're being treated with an SSRI or some other 2 antidepressant drug, not a tricyclic, that if they've been3 controlled for X period of time, and that could be 4 determined, and it doesn't change during the trial, then 5 it's fine.6 DR. FIRESTEIN: But if the mechanism of action7 of the clinical trial agent is related either to serotonin8 or norepinephrine or a variety of other --9 DR. WILLIAMS: See, I'm not as convinced as 10 some of you that SSRIs are as beneficial as tricyclics in 11 fibromyalgia.12 DR. KATZ: I think it's helpful to not lump 13 all the kinds of clinical trials together and make blanket14 rules that cover both early proof of concept trials and 15 late phase III trials because the goals of those trials 16 are different. They're testing different hypotheses, and 17 the risk to the trial of allowing potential confounders, 18 such as concomitant depression or treatment for 19 depression, is different in those two stages.20 Clearly, all these drugs and the existence of 21 concomitant co-morbidity, like moderate to severe 22 depression, is a potential confounder, and so for an early 1 257 2 1 proof of concept trial, it might be prudent to exclude 2 patients with all those issues and even maybe have a 3 shorter duration trial where you're trying to just test 4 your concept, whereas in later stages of development where5 you want to know -- and yes, the people out there in the 6 world of fibromyalgia do have depression, are on these 7 drugs, and yes, you may need to stratify it. So it may be8 appropriate to include those patients later on in drug 9 development where the generalizability of earlier findings10 to those other populations becomes the question of 11 relevance.12 DR. BRADLEY: He convinced me.13 DR. WITTER: I wonder if I could ask the chair14 to ask Drs. Crofford and Clauw to make comments on their 15 opinion as to whether opioids are effective in the sense 16 that we've been discussing today, effective for 17 fibromyalgia in terms of treating pain.18 DR. FIRESTEIN: In terms of rescue, you mean? 19 Yes, not Dr. Clauw, but Dr. Crofford, I will immediately 20 reflect that question without repeating it.21 DR. CROFFORD: Thanks, Jim.22 I actually don't think opioids are 1 258 2 1 particularly effective in this syndrome, and I would agree2 completely with whomever it was, and I think it was a 3 consensus of the panel, that opioids should not be allowed4 as rescue nor do I think it's really necessary.5 But I do think, if I could elaborate just 6 briefly, if you want to do a monotherapy trial that's 7 placebo-controlled, I think you should carefully consider 8 whether 3 or 6 months may be the most appropriate duration9 of a trial in a condition where there's no approved drug 10 and where therapies may not be particularly effective. 11 Certainly I agree with everybody that the ideal is that it12 works forever and it stays the same and the effectiveness 13 is maintained, but if you're considering a trial where you14 actually don't have concomitant meds or rescue meds, I 15 think -- and you may ask your patient -- it may or may not16 be tolerable.17 DR. FIRESTEIN: The ethics of placebo controls18 have been considered extensively in a variety of other 19 disease states, and it's even more pertinent, for 20 instance, in rheumatoid arthritis, for instance, where the21 window for being able to allow placebos has gotten 22 narrower and narrower. 1 259 2 1 In this particular instance, unlike rheumatoid2 arthritis where there is now an alternative effect of 3 therapy that can alter the natural history of the disease,4 there isn't really such a treatment right now for 5 fibromyalgia, and my guess is that most patients, when 6 they enter a study such as this, will already have been 7 tried on the standard available approaches. So I don't 8 see a particular problem with, for instance, a 6-month 9 clinical trial under those circumstances.10 DR. CROFFORD: I'm not arguing against placebo11 control. Don't misunderstand what I'm saying. In fact, 12 I'm not even arguing against a 6-month trial. I actually 13 think a 6-month trial would be useful. I'm just hoping 14 not to discourage people that may want to start clinical 15 trials from actually doing them.16 MS. MATALLANA: When we asked patients what 17 was their first choice of treatment, the number one 18 medication currently on the market was Ultram or Ultraset 19 and following that was Vicodin, Oxycontin and Darvoset. 20 But I personally feel that the reason why so many patients21 are on these narcotics is because doctors do not have many22 other options, and I know personally that I was put on a 1 260 2 1 lot of heavy narcotic medication, weaned off of it and 2 then put on basic Tylenol and Ultram and had quite a bit 3 of improvement. So I think you definitely need to take 4 them off these medications in order to see the efficacy of5 the new treatment.6 DR. FIRESTEIN: Jack?7 DR. CUSH: You could also say that people who 8 responded to your survey were Ultraset, Ultram, Vicodin 9 users and not non-steroidal Tylenol responders.10 DR. SIMON: I'd like to assure Leslie and 11 others around the table that we would not be considering 12 an active comparator trial for 6 months that would require13 true placebo in that.14 I would like to reiterate Nat's point, that we15 would like to see at some stage in development a proof of 16 concept that would demonstrate perhaps in only just 6 17 weeks, maybe even less, that there is a signal of 18 improvement that would warrant going further in 19 development to allow then the large pivotal trials to be 20 appropriately designed that would allow patients to be in 21 appropriately. So no one should think that we're 22 withholding therapy for 6 months of a period of time. 1 261 2 1 But proof of concept is a very useful way to 2 think about a short-term exposure that may allow us to get3 a real signal of real measurement that's not confounded 4 and that's always very important to have, not just for 5 efficacy but also for safety.6 DR. FIRESTEIN: Lee, I think you have to be 7 careful about referring to a placebo as withholding 8 therapy.9 DR. SIMON: Well taken.10 DR. CUSH: Lee, were you intimating that you 11 would consider an active comparator trial in an 12 environment when there is no reasonable active comparator,13 like proven efficacious standard of care, or would you 14 have to go with, as your active comparator, a drug that's 15 approved as a pain indication, for instance, albeit not 16 for fibromyalgia?17 DR. SIMON: Given the fact that this is an 18 evolving field, we would be open to any suggestion that 19 would be legitimate, that would be able to show a signal 20 of improvement, and recognizing, of course, if you're 21 doing an active comparator trial, you're going to need to 22 be superior to your active comparator if your active 1 262 2 1 comparator is not already labeled in that particular 2 field. So that then becomes standard of care or 3 "placebo." So it just depends on what you mean.4 A non-inferiority trial which obviously would 5 be very difficult to design in this construct, would 6 require a comparator that's already approved on the market7 and thus accepted. Tricyclic antidepressants would not 8 fulfill that requirement at this time.9 DR. FIRESTEIN: Nat, did you have a comment?10 DR. KATZ: I had a question for the group. I 11 know that people who in their world of rheumatology have a12 lot of experience in considering the purpose and the 13 methodology in analyzing these very long-duration trials. 14 The pain trial tradition that I come from typically uses 15 much shorter trials.16 But my question would be if the purpose of the17 trial is to show that the effect, the analgesic effect is 18 durable over time, it seems like there are a number of 19 different techniques that one could consider for 20 demonstrating that aside from having a prolonged 21 comparison, and it would also seem to me that the 22 prolonged placebo comparison as the primary means by which 1 263 2 1 to judge the durability of therapy is fraught with all 2 sorts of methodological issues. You've probably got much 3 more dropouts in your placebo group, I would think, that 4 on your active group, and you've got only the people in 5 the placebo that are placebo responders. I would ask the 6 group in rheumatology who do these sorts of things all the7 time whether you consider other alternative study designs 8 for demonstrating durability of effect, like withdrawals 9 down the line or other sorts of methods one could imagine.10 DR. FIRESTEIN: Yes, we've considered them.11 (Laughter.)12 DR. FIRESTEIN: Well, I think most of our 13 experience, in terms of these chronic disease states, 14 suggests that you really do need to have prolonged 15 treatment and that there are issues in terms of dropouts 16 that can be statistically handled, and maybe Jennifer can 17 comment on that in terms of using intention-to-treat 18 analysis and making the appropriate corrections.19 But the gold standard really has been long-20 term placebo-controlled studies for most of the agents 21 that are currently approved for chronic rheumatic 22 diseases. In particular, rheumatoid arthritis is where 1 264 2 1 there's by far the most experience but also osteoarthritis.2 DR. STAUD: I was wondering. In a disease 3 where we have no short-term knowledge of effectiveness of 4 most analgesic therapies, why we would initially go and 5 require such long-term effectiveness and not say we are 6 already happy if there is effects for 3 months instead of 7 6 months.8 DR. FIRESTEIN: Well, in part, because of the 9 rather prominent placebo effect that can occur and the 10 lack of durability of many placebo effects.11 DR. STAUD: I understand this, but we assume 12 that the trial drug will be more effective than placebo.13 DR. FIRESTEIN: Well, we don't assume that 14 actually. That's what the purpose of the study is.15 DR. STAUD: I know.16 DR. ANDERSON: I could make some comments 17 about this. Using the term "placebo-controlled trial" 18 isn't meant to mean that all therapies are withheld from 19 the placebo group because placebo, as has been discussed 20 here already, includes some background medication 21 generally these days. So although one might anticipate 22 that there would be more dropouts from the placebo group, 1 265 2 1 if you're really going to do an intent-to-treat analysis 2 and get a handle on the effectiveness of the new therapy 3 that you're looking at as distinct from its efficacy, you 4 have to include all patients for the full duration of the 5 trial. So even if people "drop out" in the sense that 6 they're no longer taking the therapy that they began with7 -- and this applies to the intervention group and the 8 control group -- you have to continue. The group that's 9 doing the trial, the sponsor, whomever, has to make every 10 possible effort to continue to get information at the 11 appropriate time points from all of the participants, so 12 that you can really do an intent-to-treat analysis. So 13 that's my shtick.14 I don't know whether I addressed what you 15 wanted me to address or not.16 DR. FIRESTEIN: Jim?17 DR. WITTER: Maybe, could you just expand a 18 bit? To some extent, there's almost some magical thinking19 when it comes to rescue medications, even the term 20 "rescue," and I think one of the ways that we need to fix 21 that, to use that term, is to keep analyzing the patients,22 even after they start taking this rescue, to give us an 1 266 2 1 idea of did it work, did it rescue. Could you maybe 2 comment on that strategy to kind of help us fill in some 3 of these blanks?4 DR. ANDERSON: Well, from what I've seen of 5 the write-ups of clinical trials, there has been a 6 tendency to just stop collecting any information on the 7 patients once they're "rescued" or deviate in any way from8 the desired protocol. But I guess my point is that you 9 really do need to keep getting the reports from them and 10 making the measurements on them, so as to do the efficacy 11 analysis and so that you can do what you're referring to, 12 to see whether this rescue was really a rescue, and you 13 can learn a lot and maybe it isn't all together in favor 14 of -- well, I don't know. Who knows what it's going to 15 show, but I don't think the sponsors should be scared of 16 doing these analyses.17 DR. WITTER: Should we be asking then sponsors18 to do that in the trials as they propose, that they look 19 at this, even if patients are rescued, they continue to 20 look at these outcomes, particularly pain?21 DR. ANDERSON: Yes, yes.22 DR. FIRESTEIN: Just to come back to the 1 267 2 1 questions, are there any concomitant therapies that should2 definitely be excluded? I think we talked a little bit 3 about this, but should tricyclics be excluded, for 4 instance?5 DR. WILLIAMS: Well, I think Jack and I both 6 have said that we thought tricyclics ought to be excluded,7 opiates ought to be excluded, and there was some 8 discussion about whether SSRIs should be excluded.9 DR. FIRESTEIN: Are there other comments from 10 the committee with regard to SSRIs, for instance?11 DR. CUSH: I would modify it according to what12 Nat said earlier, that in the short term, yes, more rigid,13 but in the long term, no, because it's more real life. I 14 think that patients on antipsychotics should be excluded. 15 I think patients with primary CNS issues, whether it was 16 meningoencephalitis, head trauma as an inciter, inciting 17 events getting in, should be excluded. I have another 18 exclusion somewhere but I can't find it right now.19 DR. FIRESTEIN: Yes?20 DR. TURK: Just a caution for us as we think 21 about excluding antidepressants or depressed patients. I 22 work in research in a tertiary care rehabilitation center, 1 268 2 1 so obviously it's a select sample, but somewhere in the 2 neighborhood of 50 to 60 percent of those patients are 3 coming into us and they're receiving antidepressant 4 medication which would mean that if we were using them in 5 clinical trials, we're basically chopping off half of the 6 sample of patients who are being treated in at least that 7 type of facility. So what you're left with is a 8 potentially unusual subsample of people with fibromyalgia.9 DR. FIRESTEIN: Is there disagreement about 10 concomitant use of tricyclics? For instance, you would 11 exclude tricyclics?12 DR. WILLIAMS: I would exclude tricyclics. I 13 actually like Nate's approach where we have proof of 14 concept and then later on, you can add some of these other15 drugs in on stable doses and see what happens with that, 16 but I think that for initial demonstration that you've got17 an effective drug, you have to exclude tricyclics.18 DR. FIRESTEIN: Right. But for registration 19 purposes later on? For phase III studies, I think it 20 would be very difficult --21 DR. WILLIAMS: -- to show you've got some 22 benefit. 1 269 2 1 DR. FIRESTEIN: One assumes that you're 2 already done a short-term proof of concept study. At that3 point, it would be very difficult to --4 DR. WILLIAMS: I think there are two studies. 5 One, you have to do without tricyclics and one you do with6 stable tricyclics.7 DR. BRADLEY: I would agree. I think 8 especially over time, I think there's a number of trials, 9 particularly Carette's trials, in the early 1990s showing 10 that the effects of the tricyclics really do fade over 11 time. After about 3 months, they really tend to fade out.12 So when you get to the longer trials, I think then it's 13 appropriate. You can include tricyclic use.14 The other issue with regard to other 15 exclusionary criteria. I'm concerned about including 16 people in trials who have had maybe even one but certainly17 multiple spinal surgeries, spinal fusions. I'm not sure 18 that the pain that those people experience is exactly the 19 same as the fibromyalgia syndrome, and I would be careful 20 about these people with really dramatic trauma done to 21 their spines.22 DR. FIRESTEIN: The point you make about the 1 270 2 1 duration of response to tricyclics also, by the way, is 2 again one of the reasons why it's important to have a 3 longer duration study.4 Well, the next question relates to ancillary 5 therapies, such as physical therapy, exercise, behavioral 6 therapy, psychotherapy, particularly for people requiring 7 dental procedures.8 (Laughter.) 9 DR. FIRESTEIN: Should that be allowed during 10 the trial?11 I think from my perspective, these things are 12 all reasonable to include.13 DR. WILLIAMS: I think it's very analogous to 14 using steroids in rheumatoid arthritis. You have them on 15 a background, but they have to be stable on that 16 background before you start the study. You can't start 17 the exercise therapy at the same time you start your 18 intervention. So as long as they're stable on those 19 backgrounds and they don't change.20 DR. FIRESTEIN: Yes?21 DR. ANDERSON: But in rheumatoid arthritis 22 trials, are people prevented from taking an exercise class 1 271 2 1 or something during the trial? Does anybody notice?2 DR. WILLIAMS: No. Often, we don't ever 3 discuss physical therapy in rheumatoid arthritis because 4 we don't think it changes the course of the disease. It 5 may change long-term mobility of the joints and so forth, 6 but it doesn't change the arthritis.7 I was more using the analogy of 8 corticosteroids, where that is an effective therapy, but 9 as long as they're on a stable dose and it's been stable 10 for 2 months and you don't change it during the course of 11 the disease, that it's allowed, and I would say if these 12 people are on these interventions mentioned here and they 13 were stable on those interventions, you can add in another14 intervention for your trial, as long as these didn't 15 change.16 You're the statistician. You look troubled.17 DR. ANDERSON: Well, I just think that -- and 18 I'm not sure that this is from a statistical point of 19 view. I don't think you should say that none of these 20 should be allowed to be started during a trial. I guess 21 if somebody starts to feel better, they may want to start 22 doing some exercise or something like that and to be 1 272 2 1 prevented from doing it because it's during a trial, I 2 think, is a problem. I just think that any of these 3 therapies that people decide to do should be noted and the4 information should be there that they've been doing them 5 and for how long as part of reporting on the trial and 6 finding out and looking at the results.7 DR. FIRESTEIN: Dr. Hoffman, then Dr. Staud.8 DR. HOFFMAN: I would agree with those 9 comments. I think it has to be approached the same way an10 adjunctive pharmaceutical therapy would be approached, 11 that if the people providing the study design feel that 12 exercise is an important adjunct to treatment, then the 13 same guidelines for exercise should be provided for 14 everyone. Everybody is being randomized to both groups. 15 It shouldn't then be a confounder.16 DR. STAUD: Yes. I can see this only works if17 the adjunctive therapies are standardized across the trial18 which I think is very difficult for psychotherapy, 19 behavioral therapy and so on, and so for this purpose, it 20 will pose a major problem.21 DR. FIRESTEIN: You think that it's a major 22 problem, did you say? 1 273 2 1 DR. STAUD: Yes, because I think the 2 standardization of these interventions across the trial is3 very difficult, and so what was mentioned here, this would4 have been part of the trial itself, that it could not be 5 just something that these subjects do on the side.6 DR. FIRESTEIN: But do you think any of these 7 have a significant impact on the disease in a short-term 8 or relatively short-term trial, like 6 months? 9 Psychotherapy for 6 months?10 DR. STAUD: CBT does. Acupuncture does. So I11 think all these things need to be considered.12 DR. WILLIAMS: I think exercise can.13 DR. FIRESTEIN: But again, it will be very 14 difficult to strap patients into a couch with a remote 15 control for the duration of the study, if part of the 16 response to the treatment would lead them to want to 17 exercise more. It would be very difficult to build in a 18 lack of exercise requirement.19 Jack?20 DR. CUSH: I agree with Roland. I think that 21 this is fraught with difficulty because you can require 22 them to have a stable course of whatever these therapies 1 274 2 1 are for 2 or 3 three months at entry, but more 2 importantly, you're going to have to continue those same 3 therapies throughout the trial, otherwise the patient is 4 in violation of the protocol and would have to be dropped,5 and so the wording should almost be written to discourage 6 such patients but you should allow them in.7 The problem in reality is that if I can get my8 patients to go to CBT or to go to yoga to Tai Chi or to go9 to a pool program, they'll do it and they'll do it for a 10 few months and then they stop doing it. They stop doing 11 it for the most minor of reasons, because they got a 12 little bit of benefit, they don't want to go any more, the13 bathing suit doesn't fit, whatever, and they stop going. 14 So they become actually quite noncompliant with a regimen 15 that has been shown to work, and you don't want to have 16 that happen in the context of the trial.17 So while you may let them in, that's well and 18 fine. One thing we didn't discuss earlier on is what's 19 the criteria by which they actually get into the study, 20 meaning we talked about ACR criteria, fine, but what's the21 activity measure that allows them to get in and that's 22 going to be an important part. So is it going to be as 1 275 2 1 simple as a VAS of greater than 4 on a 10-centimeter 2 scale. That's an important and difficult issue.3 DR. SIMON: Yes. In thinking about this 4 question, it was actually a little trick question here 5 because we actually think that cognitive and behavioral 6 therapy is not the same thing as even standardized 7 exercise. I think that we think that cognitive and 8 behavioral therapy is as therapeutic as is a tricyclic 9 antidepressant in this particular realm. I know it's hard10 for anybody to believe that I actually might say that. So11 under those circumstances, I think that we would likely 12 either stratify for that or not allow it as part of the 13 component.14 The other components, one might think about 15 this slightly differently. Perhaps if a population begins16 to exercise, perhaps that's a positive outcome and maybe 17 it's a measurable positive outcome, how much exercise they18 actually can do. We've actually thought about turning 19 that question around and using that as an additive outcome20 to be determined. So we're actually not adverse to that, 21 but we are a little adverse to leaving in cognitive and 22 behavioral therapy. 1 276 2 1 DR. FIRESTEIN: But you're quite right, it was2 not on your list of alternative therapies that would be 3 available.4 Were there a couple other comments?5 DR. BRADLEY: I guess with regard to the 6 exercise question, actually I think that perhaps it's the 7 same sort of situation that we talked before, the 8 difference between a short-term trial just as a 9 demonstration versus a longer-term trial. I think, for 10 example, it's almost like a forward pass in Woody Hayes' 11 point of view. Multiple things can go wrong. If you have12 someone who begins exercise at the start of a short 13 demonstration trial for a pharmacologic agent, one might 14 be that exercise might make the person feel better and 15 then you obscure the effect of the agent. The other is, 16 is that, oftentimes people with fibromyalgia, when they 17 begin to exercise, actually feel worse at first, and then 18 you might actually have a negative effect on your agent. 19 So I think we have to sort of make some decisions about 20 the short-term projects versus the longer-term projects.21 DR. HOFFMAN: I'm not sure adding in the 22 exercise variable really presents a problem because 1 277 2 1 patients are being randomized between groups, and if 2 they're randomized at each site, then the same standard of3 care is being provided, except for those exclusions that 4 you would want to list otherwise. So those in the placebo5 group and those in what you hope is the active drug, the 6 test drug group, have equal access to that modality and 7 that should even out in the final analysis.8 DR. STAUD: I think exercise is not the same 9 as study application. This can vary within one subject so10 dramatically over time that I think it's going to be a 11 very difficult variable to consider in this trial.12 DR. FIRESTEIN: I'm confused as to why it's 13 more difficult than in any other of the clinical trials 14 that have been evaluated. For instance, again we don't 15 prevent patients with rheumatoid arthritis from walking on16 a treadmill during a study with other anti-inflammatory 17 agents. We don't prevent them from doing that in 18 osteoarthritis. Why would we entertain that in 19 fibromyalgia? That's different from again cognitive-20 behavioral therapy. This is again part of activities of 21 daily living plus.22 DR. STAUD: I mean, part of it is that the 1 278 2 1 effect of short-term exercise is very unpredictable in 2 this patient population. So that's the main reason. So I3 think long-term exercise, doing it steadily, I think it 4 will have not dramatic impact on trials but short-term 5 starting and stopping, I could see that happening.6 DR. FIRESTEIN: Right. But we live in a real 7 world and we have to let patients seek their own level in 8 terms of activity, and if they're feeling better and they 9 want -- there will be some potentially confounding issues 10 if people are exercising more and that causes more pain 11 for other reasons because they're deconditioned or other 12 things that can cause some confounding issues, but 13 overall, this has got to be a real world trial for the 14 same reason it has to be real world with regard to 15 concomitant medications as we've talked about.16 So one or two more quick comments and then 17 we'll go on to question 6.18 MS. McBRAIR: I agree on the issue of 19 exercise. We need to allow patients to do whatever they 20 can do to help themselves, and as long as that's 21 documented, what has happened, I think we can look at it 22 more closely. But to say someone couldn't exercise or 1 279 2 1 couldn't do more and we're looking for increased function2 as one of the things we'd like to see happen, I think 3 would be a wrong message for the patients.4 DR. FIRESTEIN: The next question really 5 relates to fibromyalgia with overlap diseases and how one 6 decides clinical studies. Should patients with rheumatoid7 arthritis, lupus, Sjogren's, etc., be excluded from these 8 clinical trials?9 DR. WILLIAMS: If pain is your primary outcome10 measure, these are diseases that cause pain by a different11 mechanism, and I would exclude them.12 DR. FIRESTEIN: I would agree with that. It 13 just makes it too complicated to assess. That can be 14 something that can be done later on, but if you're looking15 for efficacy in fibromyalgia, it will make it hopelessly 16 complicated, I think. Everybody agrees with that.17 DR. WILLIAMS: If you prove its effective in 18 fibromyalgia, it'll be used in these patients anyway.19 DR. FIRESTEIN: The last question is: which 20 of the available instruments appear most appropriate for 21 evaluation of physical function, sleep disturbances, 22 cognitive impairment, and fatigue? 1 280 2 1 I would open it up. We had a number of these 2 sorts of things discussed. Anybody want to comment on 3 this?4 DR. WILLIAMS: We really discussed physical 5 function earlier, and I don't know that there's a better 6 one than the SF-36 right now for this particular disease. 7 For sleep disturbance, it was Dr. Wells that suggested the8 VAS was as effective as anything. I'm not sure I can tell9 you anything about cognitive dysfunction as a good 10 instrument. And for fatigue, I'd use the VAS.11 DR. FIRESTEIN: Any other -- yes?12 DR. TURK: At the IMMPACT meeting, when we 13 looked at the question of functional measures, we 14 separated it into disease-specific or general measures, 15 and within the general measures, we recommend that the 16 interference scale of the Multidimensional Pain Inventory 17 was as good, if not the best, measure to use, followed by 18 the BPI, or the Brief Pain Inventory. Now, the Brief Pain19 Inventory is a pain-specific measure. The Sickness Impact20 Profile, the reason we had concerns with that is because 21 the literature on its sensitivity to change is pretty poor22 and therefore it might not be the best outcome measure to 1 281 2 1 use.2 DR. CUSH: Of these, I would have physical 3 function and sleep disturbance in there. I would not do 4 cognitive impairment. I think fatigue is up in the air 5 because I think that at some point, they're all inter-6 related. You might as well add headache and irritable 7 bowel and everything else onto this. It gets a little 8 crazy with 54 visual analog scales to come up with what's 9 going on in fibromyalgia.10 I think that we should go towards a 11 responsiveness, an FM-20, if you will, that goes after 12 three domains. You must meet pain and any one of two or 13 three others. Certainly two that are potential areas are 14 pain and fatigue and quality of life or function, and to 15 improve in pain plus something else would be enough.16 Now, what you choose for each of these domains17 has got to be left up to whatever the state of the art is,18 and I think that we've heard what's reasonable as far as 19 function. I think that there are sleep scales that can be20 used or as simple as a visual analog scale. I don't know 21 that you improve things more than the visual analog scale 22 for pain and then for fatigue. There are specific fatigue 1 282 2 1 questionnaires, not well worked out, I don't think, in 2 fibromyalgia, but in other diseases they have been, like 3 cancer and whatnot.4 So they're there, and to go with, again, a 5 composite definition of response is reasonable, both for 6 short term or long term, and I think it would be a major 7 advantage or major leap forward in trying to promote drug 8 development. Again, the idea is to go after not just 9 symptom improvement but actual disease improvement, as Lee10 suggested earlier.11 DR. FIRESTEIN: But with symptom improvement 12 alone, would that not be a contribution?13 DR. CUSH: Not much more than what we've done 14 in the past or what we're currently doing because then 15 you're always talking about single symptom improvement, 16 and I think that that's a major step backwards. I think 17 that maybe we're limited by our lack of understanding of 18 disease. Nat's correlation with pneumonia was 19 interesting, but also we're in the era where we truly 20 understand the pathogenesis of pneumonia, the bugs that 21 are involved, and the consequences of pneumonia and 22 whatnot. If we were in the 18th Century, giving opium for 1 283 2 1 pneumonia would probably make a great deal of sense, and I2 think that we may well be in the 18th Century with regard 3 to fibromyalgia.4 DR. FIRESTEIN: Well, again -- 5 DR. CUSH: It's a little strong, I know.6 DR. FIRESTEIN: It is a little bit strong, and7 it's because in the end, we are in the 18th Century 8 because we don't have a specific therapy, unlike 9 pneumococcal pneumonia, and so treating symptoms alone, 10 which by the way was a gold standard for rheumatoid 11 arthritis for a long, long time -- except for injectable 12 gold, there were no disease-modifying agents, and we know 13 how good an agent injectable gold was. So just signs and 14 symptoms was good enough without having a specific 15 treatment for rheumatoid arthritis, and I think the same 16 thing might be true for improving the lives of patients 17 with fibromyalgia. Just improving the symptoms may well 18 be a significant contribution.19 Nat?20 DR. KATZ: I would just re-agree with myself 21 and with you now.22 (Laughter.) 1 284 2 1 DR. FIRESTEIN: Unlike Lee who argues with 2 himself.3 (Laughter.) 4 DR. KATZ: Before someone looks up the rules. 5 I mean, we just should keep in mind that there's been this6 traditional discordance between what's important to 7 patients and what's important to physicians. I think we 8 all have had pain at one time or another. If you can 9 recall back to when you've had pain, you'd look at pain 10 relief as being a godsend, regardless whether it improved 11 some other parameter that interested your doctor and more 12 than interested you.13 Now, again, I'm not disagreeing. I also feel 14 that ultimately, there is a notion of treatment of disease15 that obviously is the long-term goal of drug development. 16 Maybe one day, we'll understand this disease better and 17 we'll have treatments and maybe that'll be in 5 years, 18 maybe that'll be in 50 years. But in the meantime, if 19 there are agents available that can treat symptoms, that's20 what patients are really looking for.21 It's worth keeping in mind that drug 22 development has been going on for thousands of years and 1 285 2 1 effective drugs have been developed. In fact, the ones 2 that we still use for pain have been developed long before3 anybody understood anything about the diseases that were 4 being treated and anything about the mechanisms of the 5 drug and that's how these what are regarded as boons to 6 mankind have been developed.7 So to minimize the importance of treatment of 8 individual symptoms that occur in the constellation of all9 sorts of diseases would be, I think, a terrible mistake.10 DR. FIRESTEIN: Steve, and then Lee.11 DR. ABRAMSON: Yes, I would agree, and I think12 what we're really talking about is to have an isolated 13 pain indication is not necessarily unacceptable, but to 14 mandate that in all of these studies that function and 15 quality of life and all of these studies be standardized 16 so that information is captured, maybe you don't have to 17 win on all three domains, but you need to know that this 18 drug works for pain but not for function. I think over 19 time, that will be very important as these drugs sort out 20 in the market.21 I think there would be a hazard of a company 22 going just for a pain indication. I think we'll lose a 1 286 2 1 lot of information. So I think capturing information but 2 having separate indications is still important.3 DR. SIMON: Just actually as an extension, not4 to be terribly concrete, but for those of you that have 5 had experience with the Krupp Fatigue Scale as opposed to 6 a VAS scale for fatigue, might you comment on a 7 multidimensional fatigue outcome versus just are you tired8 or how you ask the question to be dependent upon one 9 question? Is there any comment about that in such an 10 issue as fatigue?11 DR. KATZ: Since it doesn't seem like anybody 12 else knows the answer, I'll chime in with this tiny amount13 of information I have. There has been a lot of instrument14 development work that's gone on in the fatigue world. 15 Talk to anybody at Ortho-McNeil Pharmaceuticals and 16 they'll tell you all about it. Initially, they started 17 with large fatigue inventories and then ultimately at 18 least their one was reduced down to the so-called Brief 19 Fatigue Inventory that's commonly used, and so in their 20 psychometric process, they were not able to effectively 21 reduce their instrument down to one item.22 DR. FIRESTEIN: Are there any other comments 1 287 2 1 on these various instruments? I don't have any.2 Jim?3 DR. WITTER: Can I recue up my question then 4 from earlier in terms of developing new instruments? 5 Dennis is here and he can comment. One of the issues, for6 example, from IMMPACT is that even though we may not have 7 an instrument, we still want the domain to be measured and8 that was the same message from the NIH conference that I 9 discussed earlier. So just because we don't have 10 something doesn't mean we don't need something in the long11 run.12 So how would you suggest as a part of the 13 discussion that we would encourage and facilitate, 14 whatever the proper term is, to get these endpoints and 15 get them validated and developed for the next generation 16 of sufferers of this condition?17 DR. FIRESTEIN: I guess you could mandate it. 18 That's what you do.19 Yes, I mean, as long as it's clear that it 20 will not be used as a club to beat them over the head with21 later if they don't hit a predetermined mark, then I think22 it's entirely reasonable to ask for the data to be 1 288 2 1 collected, but it does mean that the primary endpoints are2 going to probably have to exclude that domain. But on the3 other hand, pain and patient global is not a bad place to 4 start with fibromyalgia. Really, the question has been in5 terms of functional indices. We don't really know what to6 ask yet.7 DR. KATZ: It sounds like we're all agreeing 8 that ultimately we want to be able to measure the critical9 components of this syndrome of fibromyalgia in clinical 10 trials, even if we don't necessarily require that one win 11 on all the different components. It seems like the 12 conversation has left off is that while we think that this13 functional measure might be a good one to throw in there 14 and maybe this fatigue measure might be a good one to 15 throw in there and somehow we'll guess at what might be an16 appropriate responder index, but the fact is, as you all 17 well know in rheumatology better than I, developing such 18 instruments and such responder indices is an empiric 19 process that requires a concerted and directed effort.20 It seems reasonable to me that as part of the 21 development process of these medications, the agency is in22 a reasonable position to require that some sort of 1 289 2 1 responder index be provided which to me seems like it 2 needs to be specifically developed.3 DR. FIRESTEIN: But again, with the proviso 4 being that it's not going to be used as one of the 5 criteria for having a drug approved because you can't 6 collect the data and then retrospectively validate it and 7 then say that you either hit or miss based on those data.8 DR. KATZ: Absolutely. It has to be 9 reasonable.10 DR. STAUD: I also wanted to bring up one 11 point in the discussion that we haven't really done. This12 is measurements of disease processes that are relevant to 13 the syndrome, and as we know, the process that is relevant14 is called central sensitization, central sensitization of 15 particularly spinal cord elements as well as probably 16 higher brain centers, and currently the only measure that 17 gets even close to this is tender points that we talked 18 about.19 I think we have better measures these days 20 that we could request from companies to use as criteria in21 these trials, even if they don't make the primary 22 criteria, to look at these measures because they have 1 290 2 1 impact most likely on the evaluation of the disease and 2 its course.3 DR. CUSH: I think it's a good opportunity for4 the FDA to hear from us who are practicing clinicians what5 would be valuable and reasonable in the construct of 6 trials and indications, but I also think that a parallel 7 process should go on between the FDA and the NIH as far as8 developing a consensus group which will involve the 9 experts in the field as to what would be the most 10 discriminate values. And they'll be able to look at 11 ongoing data collection and basically do the same as the 12 way OMERACT has functioned to help rheumatoid arthritis.13 One of the problems and one of the hindrances 14 of that is that you bring together the best minds in 15 fibromyalgia research who are very biometrically oriented 16 and in the end, you get so far away from real life as far 17 as what you're requiring for outcomes, that it's only good18 for trials and drug development and it has no utility to 19 what I'm doing in my practice with my patients and the 20 extrapolatability of the information from that new trial 21 with its design to what I'm going to tell my patient and 22 what he or she may expect. 1 291 2 1 So I do think that the input of this body at 2 this point is important. I think we should push forward 3 what we think should happen, whether it's how many 4 domains, which domains, single domains, combinations of 5 domains. I think it's important that you hear, but I also6 think that another process has to complement this.7 DR. FIRESTEIN: So we've reached the end of 8 your questions. Never mind. Yes, Wendy?9 MS. McBRAIR: This isn't a question, just a 10 comment. I work with a lot of fibromyalgia patients and 11 they are looking for some answers and they are looking for12 some help. So I really commend the FDA on even bringing 13 up this discussion and starting to look for answers and 14 guidance. Along with medication control and learning more15 about what we can do to help folks, we certainly need to 16 continue to look at what the cause is of fibromyalgia and 17 hopefully some companies will continue to work on that as 18 well as some scientific researchers.19 It's very frustrating for patients to get the 20 runaround and then also to find out what they have but not21 to learn that there's some real help out there. So I hope22 that we continue this conversation. 1 292 2 1 DR. FIRESTEIN: Dr. Simon?2 DR. SIMON: Yes, we are assuaged. We want to 3 thank everybody here. We tried to construct a committee 4 that was part skeptic, part expert, part experience, and I5 think we really achieved that. Some people came totally 6 disbelieving there was any reason to have this discussion,7 I think, and I think that there were good things that were8 brought up. And most importantly, you really gave us 9 wonderful advice about what we truly are grappling with on10 a daily basis because in fact there are promising 11 therapies that are in front of us and we just didn't know 12 the kind of questions to ask, and you've helped us to be 13 able to do that.14 DR. FIRESTEIN: Thank you very much, 15 everybody. This meeting is now adjourned.16 (Whereupon, at 2:54 p.m., the committee was 17 recessed, to reconvene at 8:00 a.m., Tuesday, June 24, 18 2003.)19202122 1 293 2 12345678910111213

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